COLH_HATHI
ID COLH_HATHI Reviewed; 1021 AA.
AC Q46085;
DT 28-MAR-2018, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Collagenase ColH {ECO:0000303|PubMed:7961400};
DE EC=3.4.24.3 {ECO:0000269|PubMed:3002446};
DE AltName: Full=Class II collagenase {ECO:0000303|PubMed:6087888, ECO:0000303|PubMed:9922257};
DE AltName: Full=Gelatinase ColH {ECO:0000303|PubMed:7961400};
DE AltName: Full=Microbial collagenase;
DE Flags: Precursor;
GN Name=colH {ECO:0000303|PubMed:7961400};
OS Hathewaya histolytica (Clostridium histolyticum).
OC Bacteria; Firmicutes; Clostridia; Eubacteriales; Clostridiaceae; Hathewaya.
OX NCBI_TaxID=1498;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 41-79, FUNCTION,
RP SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE.
RC STRAIN=ATCC 19401 / DSM 2158 / JCM 1403 / NCIMB 503 / NCTC 503;
RX PubMed=7961400; DOI=10.1128/jb.176.21.6489-6496.1994;
RA Yoshihara K., Matsushita O., Minami J., Okabe A.;
RT "Cloning and nucleotide sequence analysis of the colH gene from Clostridium
RT histolyticum encoding a collagenase and a gelatinase.";
RL J. Bacteriol. 176:6489-6496(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF N-TERMINUS, DOMAIN,
RP AND PROTEOLYTIC CLEAVAGE.
RC STRAIN=ATCC 19401 / DSM 2158 / JCM 1403 / NCIMB 503 / NCTC 503;
RX PubMed=9922257; DOI=10.1128/jb.181.3.923-933.1999;
RA Matsushita O., Jung C.-M., Katayama S., Minami J., Takahashi Y., Okabe A.;
RT "Gene duplication and multiplicity of collagenases in Clostridium
RT histolyticum.";
RL J. Bacteriol. 181:923-933(1999).
RN [3]
RP COFACTOR, AND CLASSIFICATION.
RX PubMed=6087888; DOI=10.1021/bi00308a036;
RA Bond M.D., Van Wart H.E.;
RT "Characterization of the individual collagenases from Clostridium
RT histolyticum.";
RL Biochemistry 23:3085-3091(1984).
RN [4]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=3002446; DOI=10.1021/bi00344a033;
RA Mookhtiar K.A., Steinbrink D.R., Van Wart H.E.;
RT "Mode of hydrolysis of collagen-like peptides by class I and class II
RT Clostridium histolyticum collagenases: evidence for both endopeptidase and
RT tripeptidylcarboxypeptidase activities.";
RL Biochemistry 24:6527-6533(1985).
RN [5]
RP PRELIMINARY STUDIES FOR PHARMACEUTICAL USE FOR TREATMENT OF PEYRONIE
RP DISEASE.
RX PubMed=8417217; DOI=10.1016/s0022-5347(17)35998-0;
RA Gelbard M.K., James K., Riach P., Dorey F.;
RT "Collagenase versus placebo in the treatment of Peyronie's disease: a
RT double-blind study.";
RL J. Urol. 149:56-58(1993).
RN [6]
RP FUNCTION, POSSIBLE ACTIVE SITE, ACTIVITY REGULATION, DOMAIN,
RP COLLAGEN-BINDING, AND MUTAGENESIS OF GLU-456.
RC STRAIN=ATCC 19401 / DSM 2158 / JCM 1403 / NCIMB 503 / NCTC 503;
RX PubMed=9452493; DOI=10.1074/jbc.273.6.3643;
RA Matsushita O., Jung C.M., Minami J., Katayama S., Nishi N., Okabe A.;
RT "A study of the collagen-binding domain of a 116-kDa Clostridium
RT histolyticum collagenase.";
RL J. Biol. Chem. 273:3643-3648(1998).
RN [7]
RP BIOTECHNOLOGY USE IN TREATING RETAINED PLACENTA.
RX PubMed=9699958; DOI=10.1016/s0143-4004(98)90077-7;
RA Fecteau K.A., Haffner J.C., Eiler H.;
RT "The potential of collagenase as a new therapy for separation of human
RT retained placenta: hydrolytic potency on human, equine and bovine
RT placentae.";
RL Placenta 19:379-383(1998).
RN [8]
RP BIOTECHNOLOGY TO ANCHOR PROTEINS TO EXTRACELLULAR MATRIX.
RX PubMed=9618531; DOI=10.1073/pnas.95.12.7018;
RA Nishi N., Matsushita O., Yuube K., Miyanaka H., Okabe A., Wada F.;
RT "Collagen-binding growth factors: production and characterization of
RT functional fusion proteins having a collagen-binding domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:7018-7023(1998).
RN [9]
RP CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF HIS-455; GLU-456; HIS-459; ASN-479; GLU-486; GLU-487 AND
RP GLU-491.
RX PubMed=10217773; DOI=10.1128/jb.181.9.2816-2822.1999;
RA Jung C.M., Matsushita O., Katayama S., Minami J., Sakurai J., Okabe A.;
RT "Identification of metal ligands in the Clostridium histolyticum ColH
RT collagenase.";
RL J. Bacteriol. 181:2816-2822(1999).
RN [10]
RP PHARMACEUTICAL USE FOR TREATMENT OF DUPUYTREN DISEASE.
RX PubMed=10913202; DOI=10.1053/jhsu.2000.6918;
RA Badalamente M.A., Hurst L.C.;
RT "Enzyme injection as nonsurgical treatment of Dupuytren's disease.";
RL J. Hand Surg. Am. 25:629-636(2000).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND BIOTECHNOLOGY FOR ISOLATION OF PANCREAS
RP ISLET CELLS.
RX PubMed=18374061; DOI=10.1016/j.transproceed.2008.01.041;
RA McCarthy R.C., Spurlin B., Wright M.J., Breite A.G., Sturdevant L.K.,
RA Dwulet C.S., Dwulet F.E.;
RT "Development and characterization of a collagen degradation assay to assess
RT purified collagenase used in islet isolation.";
RL Transplant. Proc. 40:339-342(2008).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, DOMAIN, AND MUTAGENESIS OF GLY-426.
RX PubMed=18937627; DOI=10.1515/bc.2009.004;
RA Eckhard U., Schoenauer E., Ducka P., Briza P., Nuess D., Brandstetter H.;
RT "Biochemical characterization of the catalytic domains of three different
RT Clostridial collagenases.";
RL Biol. Chem. 390:11-18(2009).
RN [13]
RP PHARMACEUTICAL USES FOR WOUND TREATMENT AND BURN DEBRIDEMENT.
RX PubMed=19918145; DOI=10.1097/won.0b013e3181bfdd1a;
RA Shi L., Carson D.;
RT "Collagenase Santyl ointment: a selective agent for wound debridement.";
RL J. Wound Ostomy Continence Nurs. 36:S12-S16(2009).
RN [14]
RP PHARMACEUTICAL USES FOR TREATMENT OF DUPUYTREN DISEASE.
RX PubMed=19726771; DOI=10.1056/nejmoa0810866;
RG CORD I Study Group;
RA Hurst L.C., Badalamente M.A., Hentz V.R., Hotchkiss R.N., Kaplan F.T.,
RA Meals R.A., Smith T.M., Rodzvilla J.;
RT "Injectable collagenase clostridium histolyticum for Dupuytren's
RT contracture.";
RL N. Engl. J. Med. 361:968-979(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION, AND
RP BIOTECHNOLOGY FOR ISOLATION OF PANCREAS ISLET CELLS.
RX PubMed=22099748; DOI=10.1016/j.transproceed.2011.09.059;
RA Breite A.G., McCarthy R.C., Dwulet F.E.;
RT "Characterization and functional assessment of Clostridium histolyticum
RT class I (C1) collagenases and the synergistic degradation of native
RT collagen in enzyme mixtures containing class II (C2) collagenase.";
RL Transplant. Proc. 43:3171-3175(2011).
RN [16]
RP COFACTOR, AND DOMAIN.
RX PubMed=23561530; DOI=10.1016/j.bpj.2013.02.022;
RA Ohbayashi N., Matsumoto T., Shima H., Goto M., Watanabe K., Yamano A.,
RA Katoh Y., Igarashi K., Yamagata Y., Murayama K.;
RT "Solution structure of clostridial collagenase H and its calcium-dependent
RT global conformation change.";
RL Biophys. J. 104:1538-1545(2013).
RN [17]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24125730; DOI=10.1016/j.jprot.2013.10.004;
RA Eckhard U., Huesgen P.F., Brandstetter H., Overall C.M.;
RT "Proteomic protease specificity profiling of clostridial collagenases
RT reveals their intrinsic nature as dedicated degraders of collagen.";
RL J. Proteomics 100:102-114(2014).
RN [18]
RP PHARMACEUTICAL USE FOR TREATMENT OF PEYRONIE DISEASE.
RX PubMed=25711400; DOI=10.1111/bju.13096;
RA Lipshultz L.I., Goldstein I., Seftel A.D., Kaufman G.J., Smith T.M.,
RA Tursi J.P., Burnett A.L.;
RT "Clinical efficacy of collagenase Clostridium histolyticum in the treatment
RT of Peyronie's disease by subgroup: results from two large, double-blind,
RT randomized, placebo-controlled, phase III studies.";
RL BJU Int. 116:650-656(2015).
RN [19] {ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 902-1021 IN COMPLEX WITH CALCIUM,
RP COFACTOR, DOMAIN, AND COLLAGEN-BINDING.
RX PubMed=23144249; DOI=10.1128/jb.00010-12;
RA Bauer R., Wilson J.J., Philominathan S.T., Davis D., Matsushita O.,
RA Sakon J.;
RT "Structural comparison of ColH and ColG collagen-binding domains from
RT Clostridium histolyticum.";
RL J. Bacteriol. 195:318-327(2013).
RN [20] {ECO:0007744|PDB:4AR1, ECO:0007744|PDB:4ARF}
RP X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 331-721 IN PRESENCE OR ABSENCE OF
RP INHIBITOR AND IN COMPLEX WITH CALCIUM AND ZINC, FUNCTION, COFACTOR, AND
RP DOMAIN.
RX PubMed=23703618; DOI=10.1074/jbc.m112.448548;
RA Eckhard U., Schonauer E., Brandstetter H.;
RT "Structural basis for activity regulation and substrate preference of
RT clostridial collagenases G, H, and T.";
RL J. Biol. Chem. 288:20184-20194(2013).
RN [21] {ECO:0007744|PDB:4JGU, ECO:0007744|PDB:4U6T, ECO:0007744|PDB:4U7K}
RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) OF 725-810 IN COMPLEX WITH AND
RP WITHOUT CALCIUM, X-RAY CRYSTALLOGRAPHY (1.42 ANGSTROMS) OF 806-900 IN
RP COMPLEX WITH CALCIUM, COFACTOR, AND DOMAIN.
RX PubMed=25760606; DOI=10.1107/s1399004714027722;
RA Bauer R., Janowska K., Taylor K., Jordan B., Gann S., Janowski T.,
RA Latimer E.C., Matsushita O., Sakon J.;
RT "Structures of three polycystic kidney disease-like domains from
RT Clostridium histolyticum collagenases ColG and ColH.";
RL Acta Crystallogr. D 71:565-577(2015).
RN [22] {ECO:0007744|PDB:5O7E}
RP X-RAY CRYSTALLOGRAPHY (1.87 ANGSTROMS) OF 331-721 IN COMPLEX WITH CALCIUM;
RP ZINC AND INHIBITOR, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY
RP REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, BIOTECHNOLOGY FOR ANTI-INFECTIVE
RP AGENTS, AND MUTAGENESIS OF GLU-487.
RX PubMed=28820255; DOI=10.1021/jacs.7b06935;
RA Schoenauer E., Kany A.M., Haupenthal J., Huesecken K., Hoppe I.J., Voos K.,
RA Yahiaoui S., Elsaesser B., Ducho C., Brandstetter H., Hartmann R.W.;
RT "Discovery of a potent inhibitor class with high selectivity toward
RT clostridial collagenases.";
RL J. Am. Chem. Soc. 139:12696-12703(2017).
CC -!- FUNCTION: Clostridial collagenases are among the most efficient
CC degraders of eukaryotic collagen known; saprophytes use collagen as a
CC carbon source while pathogens additionally digest collagen to aid in
CC host colonization. Has both tripeptidylcarboxypeptidase on Gly-X-Y and
CC endopeptidase activities; the endopeptidase cuts within the triple
CC helix region of collagen while tripeptidylcarboxypeptidase successively
CC digests the exposed ends, thus clostridial collagenases can digest
CC large sections of collagen (PubMed:3002446). The full-length protein
CC has collagenase activity, while both the 116 kDa and 98 kDa forms act
CC on gelatin (PubMed:7961400). In vitro digestion of soluble calf skin
CC collagen fibrils requires both ColG and ColH; ColG forms missing the
CC second collagen-binding domain is also synergistic with ColH, although
CC their overall efficiency is decreased (PubMed:18374061,
CC PubMed:22099748). Digestion of collagen requires Ca(2+) and is
CC inhibited by EDTA (PubMed:9452493). The activator domain (residues 119-
CC 388) and catalytic subdomain (330-601) open and close around substrate
CC allowing digestion when the protein is closed (PubMed:23703618).
CC {ECO:0000269|PubMed:18374061, ECO:0000269|PubMed:18937627,
CC ECO:0000269|PubMed:22099748, ECO:0000269|PubMed:23703618,
CC ECO:0000269|PubMed:24125730, ECO:0000269|PubMed:28820255,
CC ECO:0000269|PubMed:3002446, ECO:0000269|PubMed:7961400,
CC ECO:0000269|PubMed:9452493}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Digestion of native collagen in the triple helical region at
CC Xaa-|-Gly bonds. With synthetic peptides, a preference is shown for
CC Gly at P3 and P1', Pro and Ala at P2 and P2', and hydroxyproline, Ala
CC or Arg at P3'.; EC=3.4.24.3; Evidence={ECO:0000269|PubMed:24125730,
CC ECO:0000269|PubMed:3002446, ECO:0000305|PubMed:10217773,
CC ECO:0000305|PubMed:18937627, ECO:0000305|PubMed:28820255};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:23144249, ECO:0000269|PubMed:23561530,
CC ECO:0000269|PubMed:23703618, ECO:0000269|PubMed:25760606,
CC ECO:0000269|PubMed:28820255, ECO:0000269|PubMed:6087888};
CC Note=Binds about 5 Ca(2+) per subunit (PubMed:6087888). The
CC metallopeptidase and PKD domains each bind 1 Ca(2+), while CDB binds 2
CC (PubMed:23144249, PubMed:23703618, PubMed:25760606, PubMed:28820255).
CC The protein is less elongated in the presence of EGTA (which chelates
CC Ca(2+)) (PubMed:23561530). {ECO:0000269|PubMed:23144249,
CC ECO:0000269|PubMed:23561530, ECO:0000269|PubMed:23703618,
CC ECO:0000269|PubMed:25760606, ECO:0000269|PubMed:28820255,
CC ECO:0000269|PubMed:6087888};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:10217773, ECO:0000269|PubMed:23703618,
CC ECO:0000269|PubMed:28820255, ECO:0000269|PubMed:6087888};
CC Note=Binds 1 Zn(2+) per subunit (PubMed:6087888, PubMed:10217773,
CC PubMed:23703618, PubMed:28820255). A fourth ligand (Asp-421) not found
CC in paralogs ColG and ColT is seen in the absence of inhibitor, which
CC probably plays a role in substrate selection (PubMed:23703618). In the
CC crystal with the N-aryl mercaptoacetamide-based inhibitor Zn is ligated
CC only by the thiolate of the inhibitor (PubMed:28820255).
CC {ECO:0000269|PubMed:10217773, ECO:0000269|PubMed:23703618,
CC ECO:0000269|PubMed:28820255, ECO:0000269|PubMed:6087888};
CC -!- ACTIVITY REGULATION: Inhibited by EDTA (PubMed:9452493). Inhibited by
CC 1-10-phenanthroline (PubMed:18937627). Inhibited by broad-spectrum zinc
CC metalloprotease inhibitor batimastat (PubMed:28820255). N-aryl
CC mercaptoacetamide-based inhibitors have been isolated that act on
CC clostridial collagenases with submicromolar affinity while having
CC negligibile activity on human collagenases (PubMed:28820255).
CC {ECO:0000269|PubMed:18937627, ECO:0000269|PubMed:28820255,
CC ECO:0000269|PubMed:9452493}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.88 mM for Pz peptide (4-phenylazobenzyloxycarbonyl-Pro-Leu-Gly-
CC Pro-D-Arg) {ECO:0000269|PubMed:10217773};
CC KM=0.269 mM for furylacryloyl-Leu-Gly-Pro-Ala (FALGPA) with a
CC catalytic fragment (residues 41-717) {ECO:0000269|PubMed:18937627};
CC KM=62 uM for (7-Methoxycoumarin-4-yl)acetyl-Ala-Gly-Pro-Pro-Gly-Pro-
CC N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl)-Gly-Arg-NH2 with
CC peptidase fragment (residues 331-721) {ECO:0000269|PubMed:28820255};
CC Vmax=12.1 umol/min/mg enzyme on FALGPA with a catalytic fragment
CC (residues 41-717) {ECO:0000269|PubMed:18937627};
CC Note=kcat is 0.11 per second on Pz peptide with whole enzyme
CC (PubMed:10217773). kcat is 15.9 per second on FALGPA with a catalytic
CC fragment (residues 41-717) (PubMed:18937627).
CC {ECO:0000269|PubMed:10217773, ECO:0000269|PubMed:18937627};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18374061,
CC ECO:0000269|PubMed:22099748, ECO:0000269|PubMed:7961400}.
CC -!- DOMAIN: The mature protein has 4 domains; a metalloprotease domain (S1,
CC approximately residues 41-717), S2a (718-810, equivalent to PKD 1), S2b
CC (811-904, equivalent to PKD 2) and a collagen-binding domain (S3, 905-
CC 1021) (PubMed:9922257, PubMed:9452493). The protein has an elongated
CC shape, which lengthens further in calcium-chelated conditions; calcium-
CC chelation also increases its susceptibility to exogenous proteases
CC (PubMed:23561530). The S1 domain has the collagen hydrolytic activity
CC (PubMed:9452493, PubMed:18937627). The metalloprotease S1 domain is
CC composed of 3 subdomains which together resemble a saddle; an activator
CC domain (residues 41-320), the catalytic peptidase subdomain (330-601)
CC and a helper subdomain (609-721) (PubMed:23703618). Unlike the S2
CC domain in ColG, upon binding to Ca(2+) the midsections of S2a and S2b
CC remain rigid; Ca(2+) binding confers thermostability (PubMed:25760606).
CC Ca(2+)-binding also alters the orientation of the N-terminal linker of
CC S2b so it lies along the long axis of the domain (PubMed:25760606). S3
CC has collagen-binding activity (PubMed:9452493). The structure of S3
CC becomes more thermostable when it is bound to Ca(2+) (PubMed:23144249).
CC Isolated CBD S3 binds unidirectionally to the C-terminus of the
CC collagen triple helix via a surface cleft (PubMed:23144249).
CC {ECO:0000269|PubMed:18937627, ECO:0000269|PubMed:23144249,
CC ECO:0000269|PubMed:23561530, ECO:0000269|PubMed:23703618,
CC ECO:0000269|PubMed:25760606, ECO:0000269|PubMed:9452493,
CC ECO:0000305|PubMed:23144249, ECO:0000305|PubMed:9452493,
CC ECO:0000305|PubMed:9922257}.
CC -!- PTM: Upon purification gives rise to 98 kDa, 105 kDa and 116 kDa (full-
CC length) proteins, all of which have the same N-terminus
CC (PubMed:7961400, PubMed:9922257). {ECO:0000269|PubMed:7961400,
CC ECO:0000269|PubMed:9922257}.
CC -!- BIOTECHNOLOGY: Widely used for tissue dissociation due to its potent
CC activity on connective tissue. {ECO:0000305}.
CC -!- BIOTECHNOLOGY: A mix of ColG and ColH is used for isolation of
CC pancreatic islet cells for subsequent transplantation.
CC {ECO:0000269|PubMed:18374061, ECO:0000269|PubMed:22099748}.
CC -!- BIOTECHNOLOGY: A mix of ColG and ColH has been used to allow release of
CC retained placenta in cows and mares, and its use in humans has been
CC proposed. {ECO:0000269|PubMed:9699958}.
CC -!- BIOTECHNOLOGY: Has been used to anchor otherwise diffusible proteins to
CC the host extracellular matrix. Fusions between the collagen-binding
CC domain (S2B plus S3) and rat epidermal growth factor or human basic
CC fibroblast growth factor (bFGF) were injected subcutaneously into adult
CC male BALB/c-nu mice. The fusion proteins remained at the sites of
CC injection for up to 10 days, and bFGF strongly stimulated fibroblast
CC growth (PubMed:9618531). {ECO:0000269|PubMed:9618531}.
CC -!- BIOTECHNOLOGY: N-aryl mercaptoacetamide-based inhibitors with
CC submicromolar affinity for clostridial collagenases but negligibile
CC activity on human collagenases have been discovered that may lead to
CC promising anti-infective drugs against Clostridia (PubMed:28820255).
CC {ECO:0000269|PubMed:28820255}.
CC -!- PHARMACEUTICAL: SANTYL Ointment (Smith and Nephew, Inc.) is indicated
CC for debriding chronic dermal ulcers and severely burned areas. It is
CC unclear which of the collagenases from this bacteria is in the
CC ointment. {ECO:0000269|PubMed:19918145}.
CC -!- PHARMACEUTICAL: Xiaflex (Endo Pharmaceuticals, Inc.) is a mix of
CC H.histolytica collagenases (ColG and ColH) used to treat both Dupuytren
CC disease and Peyronie disease. Dupuytren disease is a progressive
CC genetic disorder of pathologic collagen production and deposition under
CC the skin of the hand that causes the fingers to be drawn into the palm,
CC leading to flexion contractures of the joints, which can severely limit
CC hand function. Injections of collagenase may reduce these joint
CC contractures (PubMed:19726771, PubMed:10913202). Peyronie disease (PD)
CC is characterized by a disorganized, excessive deposition of collagen
CC that forms a plaque within the penis. The plaque restricts lengthening
CC on the affected side during erection, which can lead to penile
CC curvature deformity, discomfort and erectile dysfunction, and can
CC eventually lead to psychosocial effects such as depression and
CC relationship difficulties. Studies have shown the clinical efficacy of
CC collagenase injection for reducing penile curvature deformity and PD
CC symptom bother (PubMed:8417217, PubMed:25711400).
CC {ECO:0000269|PubMed:10913202, ECO:0000269|PubMed:19726771,
CC ECO:0000269|PubMed:25711400, ECO:0000269|PubMed:8417217}.
CC -!- MISCELLANEOUS: Clostridial collagenases enable the bacteria to
CC infiltrate and colonize host tissue, and contribute to gas gangrene
CC (myonecrosis) pathogenesis. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase M9B family. Collagenase subfamily.
CC {ECO:0000305|PubMed:6087888, ECO:0000305|PubMed:9922257}.
CC -!- WEB RESOURCE: Name=Worthington enzyme manual;
CC URL="https://www.worthington-biochem.com/CLS/";
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DR EMBL; AB014075; BAA34542.1; -; Genomic_DNA.
DR EMBL; D29981; BAA06251.1; -; Genomic_DNA.
DR PIR; I40805; I40805.
DR PDB; 3JQW; X-ray; 2.00 A; A/B/C=902-1021.
DR PDB; 3JQX; X-ray; 2.20 A; A/B/C=902-1021.
DR PDB; 4AR1; X-ray; 2.01 A; A=331-721.
DR PDB; 4ARF; X-ray; 1.77 A; A=331-721.
DR PDB; 4JGU; X-ray; 1.42 A; A/B=806-900.
DR PDB; 4U6T; X-ray; 1.76 A; A/B/C/D=725-810.
DR PDB; 4U7K; X-ray; 1.91 A; A/B/C/D/E/F/G/H=724-810.
DR PDB; 5O7E; X-ray; 1.87 A; A=331-721.
DR PDBsum; 3JQW; -.
DR PDBsum; 3JQX; -.
DR PDBsum; 4AR1; -.
DR PDBsum; 4ARF; -.
DR PDBsum; 4JGU; -.
DR PDBsum; 4U6T; -.
DR PDBsum; 4U7K; -.
DR PDBsum; 5O7E; -.
DR AlphaFoldDB; Q46085; -.
DR SASBDB; Q46085; -.
DR SMR; Q46085; -.
DR BindingDB; Q46085; -.
DR ChEMBL; CHEMBL4630869; -.
DR MEROPS; M09.003; -.
DR PRIDE; Q46085; -.
DR BRENDA; 3.4.24.3; 1481.
DR EvolutionaryTrace; Q46085; -.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0005518; F:collagen binding; IDA:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; IMP:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0034701; F:tripeptidase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0032963; P:collagen metabolic process; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR041379; ColG_subdomain.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013661; Peptidase_M9_N_dom.
DR InterPro; IPR002169; Peptidase_M9A/M9B.
DR InterPro; IPR022409; PKD/Chitinase_dom.
DR InterPro; IPR000601; PKD_dom.
DR InterPro; IPR035986; PKD_dom_sf.
DR Pfam; PF18496; ColG_sub; 1.
DR Pfam; PF01752; Peptidase_M9; 1.
DR Pfam; PF08453; Peptidase_M9_N; 1.
DR PRINTS; PR00931; MICOLLPTASE.
DR SMART; SM00089; PKD; 2.
DR SUPFAM; SSF49299; SSF49299; 2.
DR SUPFAM; SSF49899; SSF49899; 1.
DR PROSITE; PS50093; PKD; 2.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Direct protein sequencing; Hydrolase; Metal-binding;
KW Metalloprotease; Pharmaceutical; Protease; Repeat; Secreted; Signal;
KW Virulence; Zinc; Zymogen.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT PROPEP 31..40
FT /evidence="ECO:0000305|PubMed:7961400"
FT /id="PRO_0000443547"
FT CHAIN 41..1021
FT /note="Collagenase ColH"
FT /id="PRO_5010843605"
FT DOMAIN 727..808
FT /note="PKD 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00151"
FT DOMAIN 816..905
FT /note="PKD 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00151"
FT REGION 41..717
FT /note="S1 metalloprotease domain"
FT /evidence="ECO:0000305|PubMed:9452493,
FT ECO:0000305|PubMed:9922257"
FT REGION 41..320
FT /note="Activator domain"
FT /evidence="ECO:0000305|PubMed:23703618"
FT REGION 330..601
FT /note="Catalytic subdomain"
FT /evidence="ECO:0000305|PubMed:23703618"
FT REGION 609..721
FT /note="Helper subdomain"
FT /evidence="ECO:0000305|PubMed:23703618"
FT REGION 718..810
FT /note="S2a domain"
FT /evidence="ECO:0000305|PubMed:9452493,
FT ECO:0000305|PubMed:9922257"
FT REGION 811..904
FT /note="S2b domain"
FT /evidence="ECO:0000305|PubMed:9452493,
FT ECO:0000305|PubMed:9922257"
FT REGION 903..922
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 905..1021
FT /note="S3 collagen-binding domain"
FT /evidence="ECO:0000305|PubMed:9452493,
FT ECO:0000305|PubMed:9922257"
FT REGION 1002..1004
FT /note="Collagen-binding"
FT /evidence="ECO:0000250|UniProtKB:Q9X721,
FT ECO:0000303|PubMed:23144249"
FT ACT_SITE 456
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000305|PubMed:9452493"
FT BINDING 421
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0007744|PDB:4AR1"
FT BINDING 430
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0000269|PubMed:28820255, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 455
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:23703618, ECO:0000269|PubMed:28820255,
FT ECO:0000305|PubMed:10217773, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 459
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:23703618, ECO:0000269|PubMed:28820255,
FT ECO:0000305|PubMed:10217773, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 463
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0000269|PubMed:28820255, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 467
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0000269|PubMed:28820255, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 469
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0000269|PubMed:28820255, ECO:0007744|PDB:4AR1,
FT ECO:0007744|PDB:4ARF, ECO:0007744|PDB:5O7E"
FT BINDING 487
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:23703618,
FT ECO:0000269|PubMed:28820255, ECO:0000305|PubMed:10217773,
FT ECO:0007744|PDB:4AR1, ECO:0007744|PDB:4ARF,
FT ECO:0007744|PDB:5O7E"
FT BINDING 725
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4U7K"
FT BINDING 726
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4U7K"
FT BINDING 753
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4U7K"
FT BINDING 755
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4U7K"
FT BINDING 794
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4U7K"
FT BINDING 814
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4JGU"
FT BINDING 815
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4JGU"
FT BINDING 842
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4JGU"
FT BINDING 844
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4JGU"
FT BINDING 884
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:25760606,
FT ECO:0007744|PDB:4JGU"
FT BINDING 908
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW"
FT BINDING 910
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW"
FT BINDING 910
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT BINDING 912
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT BINDING 913
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT BINDING 931
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW"
FT BINDING 937
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW"
FT BINDING 937
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT BINDING 938
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT BINDING 939
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="4"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW"
FT BINDING 939
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="5"
FT /evidence="ECO:0000269|PubMed:23144249,
FT ECO:0007744|PDB:3JQW, ECO:0007744|PDB:3JQX"
FT SITE 977
FT /note="Collagen binding"
FT /evidence="ECO:0000250|UniProtKB:Q9X721,
FT ECO:0000303|PubMed:23144249"
FT MUTAGEN 426
FT /note="G->V: Loss of activity, in a catalytic fragment
FT (residues 41-717) using FALGPA as substrate."
FT /evidence="ECO:0000269|PubMed:18937627"
FT MUTAGEN 455
FT /note="H->A: No collagen degradation, about 50% zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 455
FT /note="H->F: No collagen degradation, about 10% zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 456
FT /note="E->D,Q: No collagen degradation, wild-type zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 456
FT /note="E->D: Does not degrade collagen, still binds
FT collagen."
FT /evidence="ECO:0000269|PubMed:9452493"
FT MUTAGEN 459
FT /note="H->R: No collagen degradation, about 20% zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 479
FT /note="N->A: Wild-type collagen degradation and zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 486
FT /note="E->A,Q: About 15% collagen degradation, wild-type
FT zinc content. KM for PZ peptide is wild-type, kcat
FT decreases 4-fold for Ala-486."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 486
FT /note="E->D: About 50% collagen degradation, wild-type zinc
FT content."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 487
FT /note="E->A,D,Q: Less than 5% collagen degradation, 20-42%
FT zinc content. KM for PZ peptide is 75%, kcat decreases 20-
FT fold for Gln-487."
FT /evidence="ECO:0000269|PubMed:10217773"
FT MUTAGEN 487
FT /note="E->H: Slight decrease in inhibition of collagenase
FT activity by an N-aryl mercaptoacetamide-based inhibitor."
FT /evidence="ECO:0000269|PubMed:28820255"
FT MUTAGEN 491
FT /note="E->A,D,Q: 5 to 12% collagen degradation, 70% to
FT wild-type zinc content. KM for PZ peptide is nearly wild-
FT type, kcat decreases 15-fold for Ala-491."
FT /evidence="ECO:0000269|PubMed:10217773"
FT STRAND 345..349
FT /evidence="ECO:0007829|PDB:4ARF"
FT TURN 350..353
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 354..358
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 364..385
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 391..394
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 396..398
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 399..407
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 408..414
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 415..418
FT /evidence="ECO:0007829|PDB:5O7E"
FT STRAND 423..429
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 430..432
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 434..438
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 442..444
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 449..465
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 475..480
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 483..493
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 498..500
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 506..509
FT /evidence="ECO:0007829|PDB:4ARF"
FT TURN 510..514
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 517..519
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 523..526
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 536..551
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 553..564
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 568..579
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 582..597
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 599..601
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 609..612
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 620..630
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 634..642
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 647..659
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 663..681
FT /evidence="ECO:0007829|PDB:4ARF"
FT HELIX 687..691
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 693..701
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 705..717
FT /evidence="ECO:0007829|PDB:4ARF"
FT STRAND 736..739
FT /evidence="ECO:0007829|PDB:4U6T"
FT STRAND 743..745
FT /evidence="ECO:0007829|PDB:4U7K"
FT STRAND 758..764
FT /evidence="ECO:0007829|PDB:4U6T"
FT STRAND 766..768
FT /evidence="ECO:0007829|PDB:4U6T"
FT STRAND 777..779
FT /evidence="ECO:0007829|PDB:4U7K"
FT STRAND 784..794
FT /evidence="ECO:0007829|PDB:4U6T"
FT STRAND 799..809
FT /evidence="ECO:0007829|PDB:4U6T"
FT HELIX 811..813
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 825..828
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 831..834
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 847..853
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 855..857
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 867..869
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 874..884
FT /evidence="ECO:0007829|PDB:4JGU"
FT STRAND 889..899
FT /evidence="ECO:0007829|PDB:4JGU"
FT HELIX 915..917
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 928..932
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 939..947
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 949..957
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 959..968
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 974..977
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 982..991
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 995..1005
FT /evidence="ECO:0007829|PDB:3JQW"
FT STRAND 1009..1017
FT /evidence="ECO:0007829|PDB:3JQW"
SQ SEQUENCE 1021 AA; 116377 MW; 826F45EFD96F917C CRC64;
MKRKCLSKRL MLAITMATIF TVNSTLPIYA AVDKNNATAA VQNESKRYTV SYLKTLNYYD
LVDLLVKTEI ENLPDLFQYS SDAKEFYGNK TRMSFIMDEI GRRAPQYTEI DHKGIPTLVE
VVRAGFYLGF HNKELNEINK RSFKERVIPS ILAIQKNPNF KLGTEVQDKI VSATGLLAGN
ETAPPEVVNN FTPILQDCIK NIDRYALDDL KSKALFNVLA APTYDITEYL RATKEKPENT
PWYGKIDGFI NELKKLALYG KINDNNSWII DNGIYHIAPL GKLHSNNKIG IETLTEVMKV
YPYLSMQHLQ SADQIKRHYD SKDAEGNKIP LDKFKKEGKE KYCPKTYTFD DGKVIIKAGA
RVEEEKVKRL YWASKEVNSQ FFRVYGIDKP LEEGNPDDIL TMVIYNSPEE YKLNSVLYGY
DTNNGGMYIE PEGTFFTYER EAQESTYTLE ELFRHEYTHY LQGRYAVPGQ WGRTKLYDND
RLTWYEEGGA ELFAGSTRTS GILPRKSIVS NIHNTTRNNR YKLSDTVHSK YGASFEFYNY
ACMFMDYMYN KDMGILNKLN DLAKNNDVDG YDNYIRDLSS NYALNDKYQD HMQERIDNYE
NLTVPFVADD YLVRHAYKNP NEIYSEISEV AKLKDAKSEV KKSQYFSTFT LRGSYTGGAS
KGKLEDQKAM NKFIDDSLKK LDTYSWSGYK TLTAYFTNYK VDSSNRVTYD VVFHGYLPNE
GDSKNSLPYG KINGTYKGTE KEKIKFSSEG SFDPDGKIVS YEWDFGDGNK SNEENPEHSY
DKVGTYTVKL KVTDDKGESS VSTTTAEIKD LSENKLPVIY MHVPKSGALN QKVVFYGKGT
YDPDGSIAGY QWDFGDGSDF SSEQNPSHVY TKKGEYTVTL RVMDSSGQMS EKTMKIKITD
PVYPIGTEKE PNNSKETASG PIVPGIPVSG TIENTSDQDY FYFDVITPGE VKIDINKLGY
GGATWVVYDE NNNAVSYATD DGQNLSGKFK ADKPGRYYIH LYMFNGSYMP YRINIEGSVG
R
