SAHH2_RAT
ID SAHH2_RAT Reviewed; 483 AA.
AC B5DFN2; D4A5X8;
DT 24-JUN-2015, integrated into UniProtKB/Swiss-Prot.
DT 24-JUN-2015, sequence version 2.
DT 03-AUG-2022, entry version 85.
DE RecName: Full=S-adenosylhomocysteine hydrolase-like protein 1;
DE AltName: Full=IP3R-binding protein released with inositol 1,4,5-trisphosphate;
DE AltName: Full=Putative adenosylhomocysteinase 2;
DE AltName: Full=S-adenosyl-L-homocysteine hydrolase 2;
DE Short=AdoHcyase 2;
GN Name=Ahcyl1 {ECO:0000312|RGD:1309768};
GN Synonyms=Irbit {ECO:0000303|PubMed:20584908};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116 {ECO:0000312|EMBL:AAI69126.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2-483.
RC TISSUE=Pituitary;
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 [4]
RP FUNCTION, TISSUE SPECIFICITY, AND INTERACTION WITH SLC9A3.
RX PubMed=20584908; DOI=10.1074/jbc.m110.133066;
RA He P., Klein J., Yun C.C.;
RT "Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by
RT inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with
RT IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II.";
RL J. Biol. Chem. 285:27869-27878(2010).
CC -!- FUNCTION: Multifaceted cellular regulator which coordinates several
CC essential cellular functions including regulation of epithelial HCO3(-)
CC and fluid secretion, mRNA processing and DNA replication. Regulates
CC ITPR1 sensitivity to inositol 1,4,5-trisphosphate, competing for the
CC common binding site and acting as endogenous 'pseudoligand' whose
CC inhibitory activity can be modulated by its phosphorylation status.
CC Promotes the formation of contact points between the endoplasmic
CC reticulum (ER) and mitochondria, facilitating transfer of Ca(2+) from
CC the ER to mitochondria (By similarity). Under normal cellular
CC conditions, functions cooperatively with BCL2L10 to limit ITPR1-
CC mediated Ca(2+) release but, under apoptotic stress conditions,
CC dephosphorylated which promotes dissociation of both AHCYL1 and BCL2L10
CC from mitochondria-associated endoplasmic reticulum membranes, inhibits
CC BCL2L10 interaction with ITPR1 and leads to increased Ca(2+) transfer
CC to mitochondria which promotes apoptosis (By similarity). In the
CC pancreatic and salivary ducts, at resting state, attenuates inositol
CC 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1
CC (By similarity). When extracellular stimuli induce ITPR1
CC phosphorylation or inositol 1,4,5-trisphosphate production, dissociates
CC from ITPR1 to interact with CFTR and SLC26A6, mediating their
CC synergistic activation by calcium and cAMP that stimulates the
CC epithelial secretion of electrolytes and fluid (By similarity). Also
CC activates basolateral SLC4A4 isoform 1 to coordinate fluid and HCO3(-)
CC secretion (By similarity). Inhibits the effect of STK39 on SLC4A4 and
CC CFTR by recruiting PP1 phosphatase which activates SLC4A4, SLC26A6 and
CC CFTR through dephosphorylation (By similarity). Mediates the induction
CC of SLC9A3 surface expression produced by Angiotensin-2
CC (PubMed:20584908). Depending on the cell type, activates SLC9A3 in
CC response to calcium or reverses SLC9A3R2-dependent calcium inhibition.
CC May modulate the polyadenylation state of specific mRNAs, both by
CC controlling the subcellular location of FIP1L1 and by inhibiting PAPOLA
CC activity, in response to a stimulus that alters its phosphorylation
CC state. Acts as a (dATP)-dependent inhibitor of ribonucleotide reductase
CC large subunit RRM1, controlling the endogenous dNTP pool and ensuring
CC normal cell cycle progression (By similarity). In vitro does not
CC exhibit any S-adenosyl-L-homocysteine hydrolase activity (By
CC similarity). {ECO:0000250|UniProtKB:O43865,
CC ECO:0000250|UniProtKB:Q80SW1, ECO:0000269|PubMed:20584908}.
CC -!- COFACTOR:
CC Name=NAD(+); Xref=ChEBI:CHEBI:57540;
CC Evidence={ECO:0000250|UniProtKB:O43865};
CC Note=Binds 1 NAD(+) per subunit. {ECO:0000250|UniProtKB:O43865};
CC -!- SUBUNIT: Forms multimers (By similarity). Forms heteromultimers with
CC AHCYL2 (via the C-terminal region). Interacts (when phosphorylated)
CC with ITPR1 (when not phosphorylated); the interaction suppresses
CC inositol 1,4,5-trisphosphate binding to ITPR1 (By similarity).
CC Interacts with BCL2L10; this strengthens the interaction of AHCYL1 with
CC ITPR1 (By similarity). Interacts with CFTR and SLC26A6; the
CC interactions take place once AHCYL1 is released from ITPR1 and increase
CC CFTR and SLC26A6 activities (By similarity). Interacts with RRM1; in a
CC phosphorylation- and (dATP)-dependent manner. Interacts (via PEST
CC domain when phosphorylated) with SLC4A4 isoform 1 but not isoform 2;
CC the interaction increases SLC4A4 isoform 1 activity. Interacts (when
CC phosphorylated) with SLC9A3; the interaction is required for SLC9A3
CC apical location and activity (PubMed:20584908). Interacts (when
CC phosphorylated) with FIP1L1; the interaction is direct and associates
CC AHCYL1 with the CPSF complex and RNA. Interacts with PAPOLA (By
CC similarity). Interacts with ZCCHC4 (By similarity).
CC {ECO:0000250|UniProtKB:O43865, ECO:0000250|UniProtKB:Q80SW1,
CC ECO:0000269|PubMed:20584908}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q80SW1}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:20584908}. Apical cell membrane
CC {ECO:0000269|PubMed:20584908}; Peripheral membrane protein
CC {ECO:0000305}. Microsome {ECO:0000250|UniProtKB:Q80SW1}. Note=Localizes
CC to mitochondria-associated endoplasmic reticulum membranes (MAMs) (By
CC similarity). Localization to MAMs is greatly reduced under apoptotic
CC stress conditions (By similarity). {ECO:0000250|UniProtKB:O43865}.
CC -!- TISSUE SPECIFICITY: Expressed in kidney proximal tubules and outer
CC medulla (at protein level) (PubMed:20584908).
CC {ECO:0000269|PubMed:20584908}.
CC -!- DOMAIN: The PEST region is essential for the interaction with ITPR1,
CC and, when phosphorylated, is also the RRM1-binding region. The PDZ-
CC binding region is required for maximal interaction with ITPR1 and is
CC also responsible for the IP3-insensitive interaction with ITPR1 (By
CC similarity). {ECO:0000250|UniProtKB:O43865,
CC ECO:0000250|UniProtKB:Q80SW1}.
CC -!- PTM: Phosphorylated at Ser/Thr residues between Ser-21 and Thr-25 in
CC the PEST region: required for interaction with dATP-bound RRM1 and
CC ITPR1. Phosphorylation at Ser-21 by PRKD1 and CAMK4 is required for
CC further phosphorylations by CSNK1A1. Phosphorylation is induced by
CC oxidative stress. Probably phosphorylated by CAMK2A; phosphorylation at
CC Ser-21 may be required for interaction with SLC9A3. Dephosphorylated in
CC response to apoptotic stress conditions which causes translocation of
CC both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic
CC reticulum membranes and promotes apoptosis.
CC {ECO:0000250|UniProtKB:O43865}.
CC -!- SIMILARITY: Belongs to the adenosylhomocysteinase family.
CC {ECO:0000305}.
CC -!- CAUTION: In spite of its similarity with AHCY, which catalyzes the
CC reversible hydrolysis of S-adenosyl-L-homocysteine to adenosine and
CC homocysteine, recombinant AHCYL1 expressed in bacteria shows no
CC hydrolase activity, nor does it affect the enzyme activity of AHCY.
CC {ECO:0000250|UniProtKB:Q80SW1}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EDL81885.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AABR06019878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473952; EDL81885.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC169126; AAI69126.1; -; mRNA.
DR RefSeq; NP_001102031.1; NM_001108561.1.
DR RefSeq; XP_006233227.1; XM_006233165.1.
DR RefSeq; XP_006233228.1; XM_006233166.3.
DR RefSeq; XP_008759627.1; XM_008761405.2.
DR AlphaFoldDB; B5DFN2; -.
DR SMR; B5DFN2; -.
DR IntAct; B5DFN2; 3.
DR MINT; B5DFN2; -.
DR STRING; 10116.ENSRNOP00000059145; -.
DR jPOST; B5DFN2; -.
DR PaxDb; B5DFN2; -.
DR PRIDE; B5DFN2; -.
DR GeneID; 362013; -.
DR KEGG; rno:362013; -.
DR CTD; 10768; -.
DR RGD; 1309768; Ahcyl1.
DR VEuPathDB; HostDB:ENSRNOG00000018569; -.
DR eggNOG; KOG1370; Eukaryota.
DR OMA; PVGRYKQ; -.
DR OrthoDB; 371693at2759; -.
DR Reactome; R-RNO-5578775; Ion homeostasis.
DR PRO; PR:B5DFN2; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Proteomes; UP000234681; Chromosome 2.
DR Bgee; ENSRNOG00000018569; Expressed in cerebellum and 19 other tissues.
DR ExpressionAtlas; B5DFN2; baseline and differential.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:RGD.
DR GO; GO:0044233; C:mitochondria-associated endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0038166; P:angiotensin-activated signaling pathway; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0042045; P:epithelial fluid transport; ISO:RGD.
DR GO; GO:1990456; P:mitochondrion-endoplasmic reticulum membrane tethering; ISS:UniProtKB.
DR GO; GO:0006378; P:mRNA polyadenylation; ISO:RGD.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; ISO:RGD.
DR GO; GO:0006611; P:protein export from nucleus; ISO:RGD.
DR GO; GO:0044070; P:regulation of anion transport; ISO:RGD.
DR GO; GO:0032412; P:regulation of ion transmembrane transporter activity; ISO:RGD.
DR GO; GO:0031440; P:regulation of mRNA 3'-end processing; ISO:RGD.
DR GO; GO:0051592; P:response to calcium ion; ISO:RGD.
DR GO; GO:0033353; P:S-adenosylmethionine cycle; IBA:GO_Central.
DR CDD; cd00401; SAHH; 1.
DR Gene3D; 3.40.50.1480; -; 3.
DR InterPro; IPR042172; Adenosylhomocyst_ase-like_sf.
DR InterPro; IPR000043; Adenosylhomocysteinase-like.
DR InterPro; IPR015878; Ado_hCys_hydrolase_NAD-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020082; S-Ado-L-homoCys_hydrolase_CS.
DR PANTHER; PTHR23420; PTHR23420; 1.
DR Pfam; PF05221; AdoHcyase; 1.
DR Pfam; PF00670; AdoHcyase_NAD; 1.
DR PIRSF; PIRSF001109; Ad_hcy_hydrolase; 1.
DR SMART; SM00996; AdoHcyase; 1.
DR SMART; SM00997; AdoHcyase_NAD; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR TIGRFAMs; TIGR00936; ahcY; 1.
DR PROSITE; PS00738; ADOHCYASE_1; 1.
DR PROSITE; PS00739; ADOHCYASE_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cytoplasm; Endoplasmic reticulum; Membrane; Microsome; NAD;
KW One-carbon metabolism; Phosphoprotein; Reference proteome; RNA-binding.
FT CHAIN 1..483
FT /note="S-adenosylhomocysteine hydrolase-like protein 1"
FT /id="PRO_0000433356"
FT REGION 1..56
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 18..45
FT /note="PEST"
FT /evidence="ECO:0000250|UniProtKB:O43865,
FT ECO:0000250|UniProtKB:Q80SW1"
FT REGION 91..154
FT /note="Interaction with BCL2L10"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT REGION 234..401
FT /note="NAD binding"
FT /evidence="ECO:0000250"
FT REGION 473..483
FT /note="PDZ-binding"
FT /evidence="ECO:0000250"
FT COMPBIAS 1..38
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 108
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 182
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 207
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 237
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 241
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 271..275
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT BINDING 294
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT BINDING 329
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT BINDING 350..352
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT MOD_RES 21
FT /note="Phosphoserine; by PKD"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT MOD_RES 24
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT MOD_RES 27
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT MOD_RES 30
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43865"
FT MOD_RES 37
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80SW1"
FT MOD_RES 344
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43865"
SQ SEQUENCE 483 AA; 53753 MW; 18DFC7E74697E1D4 CRC64;
MQEFTKFPTK TGRRSLSRSI SQSSTDSYSS AASYTDSSDD EVSPREKQQT NSKGSSNFCV
KNIKQAEFGR REIEIAEQDM SALISLRKRA QGEKPLAGAK IVGCTHITAQ TAVLIETLCA
LGAQCRWSAC NIYSTQNEVA AALAEAGVAV FAWKGESEDD FWWCIDRCVN MDGWQANMIL
DDGGDLTHWV YKKYPNVFKK IRGIVEESVT GVHRLYQLSK AGKLCVPAMN VNDSVTKQKF
DNLYCCRESI LDGLKRTTDV MFGGKQVVVC GYGEVGKGCC AALKALGAIV YITEIDPICA
LQACMDGFRV VKLNEVIRQV DVVITCTGNK NVVTREHLDR MKNSCIVCNM GHSNTEIDVT
SLRTPELTWE RVRSQVDHVI WPDGKRVVLL AEGRLLNLSC STVPTFVLSI TATTQALALI
ELYNAPEGRY KQDVYLLPKK MDEYVASLHL PSFDAHLTEL TDDQAKYLGL NKNGPFKPNY
YRY
