FA20C_HUMAN
ID FA20C_HUMAN Reviewed; 584 AA.
AC Q8IXL6; A4D2Q5; L8B5W8; Q5I0W9; Q7Z4I0; Q9NPT2;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 05-APR-2011, sequence version 2.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Extracellular serine/threonine protein kinase FAM20C {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:29858230, ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020};
DE AltName: Full=Dentin matrix protein 4 {ECO:0000250|UniProtKB:Q5MJS3};
DE Short=DMP-4 {ECO:0000250|UniProtKB:Q5MJS3};
DE AltName: Full=Golgi casein kinase {ECO:0000303|PubMed:22582013};
DE AltName: Full=Golgi-enriched fraction casein kinase {ECO:0000303|PubMed:22582013};
DE Short=GEF-CK {ECO:0000303|PubMed:22582013};
DE Flags: Precursor;
GN Name=FAM20C {ECO:0000312|HGNC:HGNC:22140};
GN Synonyms=DMP4 {ECO:0000250|UniProtKB:Q5MJS3};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Wu C., Ding P., Han W., Rui M., Wang Y., Song Q., Ma D.;
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Kitagawa H., Izumikawa T., Koike T.;
RT "Molecular cloning and characterization of a novel xylosylkinase.";
RL Submitted (FEB-2010) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, SUBCELLULAR LOCATION,
RP AUTOPHOSPHORYLATION, GLYCOSYLATION AT ASN-101; ASN-335 AND ASN-470, AND
RP MUTAGENESIS OF 93-LEU--ASP-95; ASN-101; ASN-335; ASN-470 AND ASP-478.
RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
RA Pinna L.A., Pagliarini D.J., Dixon J.E.;
RT "A single kinase generates the majority of the secreted phosphoproteome.";
RL Cell 161:1619-1632(2015).
RN [9]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT,
RP INTERACTION WITH MBTPS1; SEC23A AND SEC24A, SUBCELLULAR LOCATION, TOPOLOGY,
RP AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-106, AND MUTAGENESIS OF
RP 28-ASP--PRO-31; CYS-46; CYS-48; ARG-89; ILE-90; LEU-91; GLN-92; SER-106 AND
RP ASP-478.
RX PubMed=34349020; DOI=10.1073/pnas.2100133118;
RA Chen X., Zhang J., Liu P., Wei Y., Wang X., Xiao J., Wang C.C., Wang L.;
RT "Proteolytic processing of secretory pathway kinase Fam20C by site-1
RT protease promotes biomineralization.";
RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
RN [10]
RP TISSUE SPECIFICITY.
RX PubMed=15676076; DOI=10.1186/1471-2164-6-11;
RA Nalbant D., Youn H., Nalbant S.I., Sharma S., Cobos E., Beale E.G., Du Y.,
RA Williams S.C.;
RT "FAM20: an evolutionarily conserved family of secreted proteins expressed
RT in hematopoietic cells.";
RL BMC Genomics 6:11-11(2005).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-470.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, MANGANESE-BINDING, MUTAGENESIS OF ASP-478,
RP VARIANTS RNS ASN-258; ARG-280; SER-328; ARG-379; GLU-379; ARG-388; ASN-451
RP AND TRP-549, AND CHARACTERIZATION OF VARIANTS RNS SER-328 AND ASN-451.
RX PubMed=22582013; DOI=10.1126/science.1217817;
RA Tagliabracci V.S., Engel J.L., Wen J., Wiley S.E., Worby C.A., Kinch L.N.,
RA Xiao J., Grishin N.V., Dixon J.E.;
RT "Secreted kinase phosphorylates extracellular proteins that regulate
RT biomineralization.";
RL Science 336:1150-1153(2012).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR,
RP ACTIVE SITE, AND MUTAGENESIS OF LYS-271; LYS-285; GLU-306; GLU-311;
RP ARG-408; ASP-458 AND ASP-458.
RX PubMed=23754375; DOI=10.1073/pnas.1309211110;
RA Xiao J., Tagliabracci V.S., Wen J., Kim S.A., Dixon J.E.;
RT "Crystal structure of the Golgi casein kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:10574-10579(2013).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH FAM20A,
RP MUTAGENESIS OF GLU-306 AND ASP-478, VARIANTS RNS MET-268 AND SER-328, AND
RP CHARACTERIZATION OF VARIANTS RNS MET-268 AND SER-328.
RX PubMed=25789606; DOI=10.7554/elife.06120;
RA Cui J., Xiao J., Tagliabracci V.S., Wen J., Rahdar M., Dixon J.E.;
RT "A secretory kinase complex regulates extracellular protein
RT phosphorylation.";
RL Elife 4:0-0(2015).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-478.
RX PubMed=29858230; DOI=10.15252/embj.201798699;
RA Zhang J., Zhu Q., Wang X., Yu J., Chen X., Wang J., Wang X., Xiao J.,
RA Wang C.C., Wang L.;
RT "Secretory kinase Fam20C tunes endoplasmic reticulum redox state via
RT phosphorylation of Ero1alpha.";
RL EMBO J. 37:0-0(2018).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=32149426; DOI=10.15252/embj.2019103841;
RA Yu J., Li T., Liu Y., Wang X., Zhang J., Wang X., Shi G., Lou J., Wang L.,
RA Wang C.C., Wang L.;
RT "Phosphorylation switches protein disulfide isomerase activity to maintain
RT proteostasis and attenuate ER stress.";
RL EMBO J. 39:e103841-e103841(2020).
RN [17]
RP VARIANTS RNS ARG-379; GLU-379; ARG-388 AND TRP-549.
RX PubMed=17924334; DOI=10.1086/522240;
RA Simpson M.A., Hsu R., Keir L.S., Hao J., Sivapalan G., Ernst L.M.,
RA Zackai E.H., Al-Gazali L.I., Hulskamp G., Kingston H.M., Prescott T.E.,
RA Ion A., Patton M.A., Murday V., George A., Crosby A.H.;
RT "Mutations in FAM20C are associated with lethal osteosclerotic bone
RT dysplasia (Raine syndrome), highlighting a crucial molecule in bone
RT development.";
RL Am. J. Hum. Genet. 81:906-912(2007).
CC -!- FUNCTION: Golgi serine/threonine protein kinase that phosphorylates
CC secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key
CC role in biomineralization of bones and teeth (PubMed:22582013,
CC PubMed:23754375, PubMed:25789606). Constitutes the main protein kinase
CC for extracellular proteins, generating the majority of the
CC extracellular phosphoproteome (PubMed:26091039). Mainly phosphorylates
CC proteins within the Ser-x-Glu/pSer motif, but also displays a broader
CC substrate specificity (PubMed:26091039). Phosphorylates ERO1A,
CC enhancing its activity which is required to maintain endoplasmic
CC reticulum redox homeostasis and for oxidative protein folding
CC (PubMed:29858230, PubMed:34349020). During endoplasmic reticulum
CC stress, phosphorylates P4HB/PDIA1 which induces a functional switch,
CC causing P4HB to change from an oxidoreductase to a molecular chaperone
CC (PubMed:32149426). This is critical to maintain ER proteostasis and
CC reduce cell death under ER stress (PubMed:32149426). Phosphorylation of
CC P4HB also promotes its interaction with ERN1, leading to reduced
CC activity of ERN1, a key sensor for the endoplasmic reticulum unfolded
CC protein response (PubMed:32149426). Required for osteoblast
CC differentiation and mineralization (PubMed:34349020). Phosphorylates
CC casein as well as a number of proteins involved in biomineralization
CC such as AMELX, AMTN, ENAM and SPP1/OPN (PubMed:22582013,
CC PubMed:25789606, PubMed:34349020). In addition to its role in
CC biomineralization, also plays a role in lipid homeostasis, wound
CC healing and cell migration and adhesion (PubMed:26091039).
CC {ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375,
CC ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:26091039,
CC ECO:0000269|PubMed:29858230, ECO:0000269|PubMed:32149426,
CC ECO:0000269|PubMed:34349020}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:23754375,
CC ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:29858230,
CC ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:22582013,
CC ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:23754375, ECO:0000305|PubMed:22582013};
CC -!- ACTIVITY REGULATION: Serine/threonine protein kinase activity is
CC increased upon interaction with FAM20A. {ECO:0000269|PubMed:25789606}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.8 uM for manganese/ATP {ECO:0000269|PubMed:23754375};
CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:34349020). Interacts with
CC FAM20A; probably forming a heterotetramer of 2 subunits of FAM20A and 2
CC subunits of FAM20C (PubMed:25789606). Interacts with protease
CC MBTPS1/S1P; the interaction results in FAM20C cleavage and secretion
CC (PubMed:34349020). Interacts with COPII components SEC23A and SEC24A;
CC transport of FAM20C from the endoplasmic reticulum to the Golgi is
CC likely to be mediated by COPII vesicles (PubMed:34349020).
CC {ECO:0000269|PubMed:25789606, ECO:0000269|PubMed:34349020}.
CC -!- INTERACTION:
CC Q8IXL6; Q9NP70: AMBN; NbExp=2; IntAct=EBI-7147442, EBI-11893530;
CC Q8IXL6; Q6UX39: AMTN; NbExp=2; IntAct=EBI-7147442, EBI-11892684;
CC Q8IXL6; O14791: APOL1; NbExp=2; IntAct=EBI-7147442, EBI-1221934;
CC Q8IXL6; P05060: CHGB; NbExp=2; IntAct=EBI-7147442, EBI-712619;
CC Q8IXL6; Q9NRM1: ENAM; NbExp=2; IntAct=EBI-7147442, EBI-11892601;
CC Q8IXL6; Q96MK3: FAM20A; NbExp=3; IntAct=EBI-7147442, EBI-11892970;
CC Q8IXL6; P02671: FGA; NbExp=2; IntAct=EBI-7147442, EBI-348571;
CC Q8IXL6; P08833: IGFBP1; NbExp=2; IntAct=EBI-7147442, EBI-13646303;
CC Q8IXL6; P02810: PRH2; NbExp=2; IntAct=EBI-7147442, EBI-738601;
CC Q8IXL6; P01008: SERPINC1; NbExp=2; IntAct=EBI-7147442, EBI-1039832;
CC Q8IXL6; P10451: SPP1; NbExp=3; IntAct=EBI-7147442, EBI-723648;
CC Q8IXL6; PRO_0000020321 [P10451]: SPP1; NbExp=2; IntAct=EBI-7147442, EBI-11893188;
CC Q8IXL6; P02666: CSN2; Xeno; NbExp=3; IntAct=EBI-7147442, EBI-5260183;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC {ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}; Single-pass
CC type II membrane protein {ECO:0000269|PubMed:34349020}. Secreted
CC {ECO:0000269|PubMed:26091039}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:32149426}. Note=Resides in the Golgi apparatus
CC membrane and is secreted following propeptide cleavage
CC (PubMed:34349020). Retained in the endoplasmic reticulum (ER) in
CC response to ER stress where it phosphorylates P4HB (PubMed:32149426).
CC {ECO:0000269|PubMed:32149426, ECO:0000269|PubMed:34349020}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8IXL6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IXL6-2; Sequence=VSP_040834;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:15676076}.
CC -!- PTM: N-glycosylation is required for folding.
CC {ECO:0000305|PubMed:26091039}.
CC -!- PTM: Autophosphorylated. {ECO:0000269|PubMed:26091039,
CC ECO:0000269|PubMed:34349020}.
CC -!- PTM: Propeptide cleavage by MBTPS1/S1P promotes FAM20C secretion and
CC maximal kinase activity which is essential for efficient osteoblast
CC differentiation and biomineralization. {ECO:0000269|PubMed:34349020}.
CC -!- DISEASE: Raine syndrome (RNS) [MIM:259775]: Autosomal recessive
CC osteosclerotic bone dysplasia with neonatal lethal outcome. Clinical
CC features include generalized osteosclerosis, craniofacial dysplasia and
CC microcephaly. {ECO:0000269|PubMed:17924334,
CC ECO:0000269|PubMed:22582013, ECO:0000269|PubMed:25789606}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the FAM20 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH40074.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=EAL23705.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF533706; AAQ09019.1; -; mRNA.
DR EMBL; AB545605; BAM78534.1; -; mRNA.
DR EMBL; AC093627; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC145676; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC187652; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236966; EAL23705.1; ALT_INIT; Genomic_DNA.
DR EMBL; CH471144; EAW87149.1; -; Genomic_DNA.
DR EMBL; BC040074; AAH40074.1; ALT_INIT; mRNA.
DR EMBL; BC087853; AAH87853.1; -; mRNA.
DR EMBL; AL390147; CAB99089.2; -; mRNA.
DR CCDS; CCDS47522.1; -. [Q8IXL6-1]
DR PIR; T51872; T51872.
DR RefSeq; NP_064608.2; NM_020223.3. [Q8IXL6-1]
DR PDB; 5YH3; X-ray; 3.30 A; C/D=141-578.
DR PDBsum; 5YH3; -.
DR AlphaFoldDB; Q8IXL6; -.
DR SMR; Q8IXL6; -.
DR BioGRID; 121294; 190.
DR IntAct; Q8IXL6; 76.
DR MINT; Q8IXL6; -.
DR STRING; 9606.ENSP00000322323; -.
DR GlyConnect; 1230; 11 N-Linked glycans (2 sites).
DR GlyGen; Q8IXL6; 8 sites, 11 N-linked glycans (2 sites), 1 O-linked glycan (5 sites).
DR iPTMnet; Q8IXL6; -.
DR PhosphoSitePlus; Q8IXL6; -.
DR BioMuta; FAM20C; -.
DR DMDM; 327478506; -.
DR EPD; Q8IXL6; -.
DR jPOST; Q8IXL6; -.
DR MassIVE; Q8IXL6; -.
DR MaxQB; Q8IXL6; -.
DR PaxDb; Q8IXL6; -.
DR PeptideAtlas; Q8IXL6; -.
DR PRIDE; Q8IXL6; -.
DR ProteomicsDB; 71022; -. [Q8IXL6-1]
DR ProteomicsDB; 71023; -. [Q8IXL6-2]
DR Antibodypedia; 5456; 153 antibodies from 24 providers.
DR DNASU; 56975; -.
DR Ensembl; ENST00000313766.6; ENSP00000322323.5; ENSG00000177706.9. [Q8IXL6-1]
DR Ensembl; ENST00000672066.1; ENSP00000499851.1; ENSG00000288499.1. [Q8IXL6-1]
DR GeneID; 56975; -.
DR KEGG; hsa:56975; -.
DR MANE-Select; ENST00000313766.6; ENSP00000322323.5; NM_020223.4; NP_064608.2.
DR UCSC; uc003sip.4; human. [Q8IXL6-1]
DR CTD; 56975; -.
DR DisGeNET; 56975; -.
DR GeneCards; FAM20C; -.
DR HGNC; HGNC:22140; FAM20C.
DR HPA; ENSG00000177706; Low tissue specificity.
DR MalaCards; FAM20C; -.
DR MIM; 259775; phenotype.
DR MIM; 611061; gene.
DR neXtProt; NX_Q8IXL6; -.
DR OpenTargets; ENSG00000177706; -.
DR Orphanet; 1832; Lethal osteosclerotic bone dysplasia.
DR PharmGKB; PA134898453; -.
DR VEuPathDB; HostDB:ENSG00000177706; -.
DR eggNOG; KOG3829; Eukaryota.
DR GeneTree; ENSGT00950000182951; -.
DR HOGENOM; CLU_028926_2_0_1; -.
DR InParanoid; Q8IXL6; -.
DR OMA; AGRMINM; -.
DR OrthoDB; 484324at2759; -.
DR PhylomeDB; Q8IXL6; -.
DR TreeFam; TF313276; -.
DR PathwayCommons; Q8IXL6; -.
DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR SABIO-RK; Q8IXL6; -.
DR SignaLink; Q8IXL6; -.
DR SIGNOR; Q8IXL6; -.
DR BioGRID-ORCS; 56975; 15 hits in 1081 CRISPR screens.
DR GeneWiki; FAM20C; -.
DR GenomeRNAi; 56975; -.
DR Pharos; Q8IXL6; Tbio.
DR PRO; PR:Q8IXL6; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q8IXL6; protein.
DR Bgee; ENSG00000177706; Expressed in right lobe of liver and 98 other tissues.
DR Genevisible; Q8IXL6; HS.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0030173; C:integral component of Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IEA:Ensembl.
DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB.
DR GO; GO:0016773; F:phosphotransferase activity, alcohol group as acceptor; IBA:GO_Central.
DR GO; GO:0002020; F:protease binding; IPI:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0043621; F:protein self-association; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0031214; P:biomineral tissue development; IMP:UniProtKB.
DR GO; GO:0097187; P:dentinogenesis; IEA:Ensembl.
DR GO; GO:0070166; P:enamel mineralization; IBA:GO_Central.
DR GO; GO:0071895; P:odontoblast differentiation; IEA:Ensembl.
DR GO; GO:0036179; P:osteoclast maturation; IEA:Ensembl.
DR GO; GO:0030501; P:positive regulation of bone mineralization; IEA:Ensembl.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0040036; P:regulation of fibroblast growth factor receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0051174; P:regulation of phosphorus metabolic process; IEA:Ensembl.
DR InterPro; IPR024869; FAM20.
DR InterPro; IPR009581; FAM20_C.
DR PANTHER; PTHR12450; PTHR12450; 1.
DR Pfam; PF06702; Fam20C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Biomineralization;
KW Calcium; Direct protein sequencing; Disease variant; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Kinase; Manganese;
KW Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Secreted; Serine/threonine-protein kinase;
KW Signal-anchor; Transferase; Transmembrane; Transmembrane helix.
FT PROPEP 1..92
FT /evidence="ECO:0000269|PubMed:26091039,
FT ECO:0000269|PubMed:34349020"
FT /id="PRO_0000433883"
FT CHAIN 93..584
FT /note="Extracellular serine/threonine protein kinase
FT FAM20C"
FT /id="PRO_0000008747"
FT TOPO_DOM 1..10
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 11..31
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 32..584
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT REGION 62..81
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 94..159
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 354..565
FT /note="Kinase domain"
FT /evidence="ECO:0000305|PubMed:22582013"
FT COMPBIAS 118..144
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 458
FT /evidence="ECO:0000269|PubMed:23754375"
FT BINDING 269
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 285
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 306
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 306
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 389..392
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 463
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 478
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT BINDING 478
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000305|PubMed:22582013"
FT SITE 92..93
FT /note="Cleavage; by MBTPS1"
FT /evidence="ECO:0000269|PubMed:34349020"
FT MOD_RES 106
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:34349020"
FT CARBOHYD 101
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26091039"
FT CARBOHYD 335
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26091039"
FT CARBOHYD 470
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218,
FT ECO:0000269|PubMed:26091039"
FT DISULFID 46
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:34349020"
FT DISULFID 48
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:34349020"
FT DISULFID 362..378
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT DISULFID 367..371
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT DISULFID 426..500
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT DISULFID 501..560
FT /evidence="ECO:0000250|UniProtKB:Q9XTW2"
FT VAR_SEQ 1..332
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_040834"
FT VARIANT 258
FT /note="I -> N (in RNS)"
FT /evidence="ECO:0000269|PubMed:22582013"
FT /id="VAR_073660"
FT VARIANT 268
FT /note="T -> M (in RNS; mild non-lethal form; decreased
FT protein kinase activity; dbSNP:rs778899041)"
FT /evidence="ECO:0000269|PubMed:25789606"
FT /id="VAR_073661"
FT VARIANT 280
FT /note="G -> R (in RNS; dbSNP:rs779708323)"
FT /evidence="ECO:0000269|PubMed:22582013"
FT /id="VAR_073662"
FT VARIANT 328
FT /note="P -> S (in RNS; mild non-lethal form; decreased
FT protein kinase activity; FAM20A is still able to increase
FT remaining protein kinase activity; dbSNP:rs797044462)"
FT /evidence="ECO:0000269|PubMed:22582013,
FT ECO:0000269|PubMed:25789606"
FT /id="VAR_073663"
FT VARIANT 379
FT /note="G -> E (in RNS; dbSNP:rs796051852)"
FT /evidence="ECO:0000269|PubMed:17924334,
FT ECO:0000269|PubMed:22582013"
FT /id="VAR_037530"
FT VARIANT 379
FT /note="G -> R (in RNS)"
FT /evidence="ECO:0000269|PubMed:17924334,
FT ECO:0000269|PubMed:22582013"
FT /id="VAR_037531"
FT VARIANT 388
FT /note="L -> R (in RNS; dbSNP:rs796051849)"
FT /evidence="ECO:0000269|PubMed:17924334,
FT ECO:0000269|PubMed:22582013"
FT /id="VAR_037532"
FT VARIANT 451
FT /note="D -> N (in RNS; mild non-lethal form; decreased
FT protein kinase activity)"
FT /evidence="ECO:0000269|PubMed:22582013"
FT /id="VAR_073664"
FT VARIANT 549
FT /note="R -> W (in RNS; dbSNP:rs796051850)"
FT /evidence="ECO:0000269|PubMed:17924334,
FT ECO:0000269|PubMed:22582013"
FT /id="VAR_037533"
FT MUTAGEN 28..31
FT /note="DLLP->AAAA: Loss of membrane localization with more
FT efficient secretion and loss of propeptide cleavage.
FT Reduced oligomerization."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 46
FT /note="C->S: No effect on homodimer formation. Complete
FT disruption of homodimer formation but no effect on
FT secretion; when associated with S-48."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 48
FT /note="C->S: No effect on homodimer formation. Complete
FT disruption of homodimer formation but no effect on
FT secretion; when associated with S-46."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 89
FT /note="R->A: Impaired secretion. Loss of ability to promote
FT osteoblast differentiation; when associated with A-92."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 90
FT /note="I->A: No effect on secretion."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 91..93
FT /note="LQD->AAA: No effect on secretion or activity."
FT /evidence="ECO:0000269|PubMed:26091039"
FT MUTAGEN 91
FT /note="L->S: Impaired secretion."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 92
FT /note="Q->A: Impaired secretion. Loss of ability to promote
FT osteoblast differentiation; when associated with A-89."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 101
FT /note="N->A: Impaired secretion; when associated with A-335
FT and A-470."
FT /evidence="ECO:0000269|PubMed:26091039"
FT MUTAGEN 106
FT /note="S->A: Abolishes phosphorylation."
FT /evidence="ECO:0000269|PubMed:34349020"
FT MUTAGEN 271
FT /note="K->A: Reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375"
FT MUTAGEN 285
FT /note="K->A: Reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375"
FT MUTAGEN 306
FT /note="E->A,Q: Strongly reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375,
FT ECO:0000269|PubMed:25789606"
FT MUTAGEN 311
FT /note="E->A: Reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375"
FT MUTAGEN 335
FT /note="N->A: Impaired secretion; when associated with A-101
FT and A-470."
FT /evidence="ECO:0000269|PubMed:26091039"
FT MUTAGEN 408
FT /note="R->A: Reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375"
FT MUTAGEN 458
FT /note="D->A: Abrogates kinase activity."
FT /evidence="ECO:0000269|PubMed:23754375"
FT MUTAGEN 470
FT /note="N->A: Impaired secretion; when associated with A-101
FT and A-335."
FT /evidence="ECO:0000269|PubMed:26091039"
FT MUTAGEN 478
FT /note="D->A: Unable to bind manganese. Abrogates kinase
FT activity. Loss of ERO1A phosphorylation. Loss of
FT autophosphorylation. Loss of ability to promote osteoblast
FT differentiation."
FT /evidence="ECO:0000269|PubMed:22582013,
FT ECO:0000269|PubMed:23754375, ECO:0000269|PubMed:25789606,
FT ECO:0000269|PubMed:26091039, ECO:0000269|PubMed:29858230,
FT ECO:0000269|PubMed:34349020"
FT CONFLICT 274..288
FT /note="MTFQNYGQALFKPMK -> FLSDKPFLFLSCFLR (in Ref. 6;
FT CAB99089)"
FT /evidence="ECO:0000305"
FT CONFLICT 564
FT /note="N -> D (in Ref. 5; AAH87853 and 6; CAB99089)"
FT /evidence="ECO:0000305"
FT HELIX 160..164
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 168..170
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 179..181
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 225..231
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 237..239
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 244..255
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 258..263
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 272..276
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 281..286
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 301..303
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 308..320
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 329..335
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 336..340
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 341..343
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 347..350
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 361..363
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 368..370
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 373..375
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 380..390
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 419..421
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 423..425
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 426..429
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 433..436
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 438..454
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 461..463
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 467..470
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 491..494
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 495..500
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 505..513
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 517..519
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 521..528
FT /evidence="ECO:0007829|PDB:5YH3"
FT STRAND 530..534
FT /evidence="ECO:0007829|PDB:5YH3"
FT HELIX 540..564
FT /evidence="ECO:0007829|PDB:5YH3"
FT TURN 567..569
FT /evidence="ECO:0007829|PDB:5YH3"
SQ SEQUENCE 584 AA; 66234 MW; ECD278B5EA681FEF CRC64;
MKMMLVRRFR VLILMVFLVA CALHIALDLL PRLERRGARP SGEPGCSCAQ PAAEVAAPGW
AQVRGRPGEP PAASSAAGDA GWPNKHTLRI LQDFSSDPSS NLSSHSLEKL PPAAEPAERA
LRGRDPGALR PHDPAHRPLL RDPGPRRSES PPGPGGDASL LARLFEHPLY RVAVPPLTEE
DVLFNVNSDT RLSPKAAENP DWPHAGAEGA EFLSPGEAAV DSYPNWLKFH IGINRYELYS
RHNPAIEALL HDLSSQRITS VAMKSGGTQL KLIMTFQNYG QALFKPMKQT REQETPPDFF
YFSDYERHNA EIAAFHLDRI LDFRRVPPVA GRMVNMTKEI RDVTRDKKLW RTFFISPANN
ICFYGECSYY CSTEHALCGK PDQIEGSLAA FLPDLSLAKR KTWRNPWRRS YHKRKKAEWE
VDPDYCEEVK QTPPYDSSHR ILDVMDMTIF DFLMGNMDRH HYETFEKFGN ETFIIHLDNG
RGFGKYSHDE LSILVPLQQC CRIRKSTYLR LQLLAKEEYK LSLLMAESLR GDQVAPVLYQ
PHLEALDRRL RVVLKAVRDC VERNGLHSVV DDDLDTEHRA ASAR
