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2.A.4.3.5
Homodimeric solute carrier family 30 (zinc transporter), member 8, ZnT8 or ZnT-8.  An inherited R325W mutant gives aberant zinc transport in pancreatic beta cells (Weijers 2010). It is chiefly expressed in pancreatic islet cells, where it mediates zinc (Zn2+) uptake into secretory granules. It plays a role in glucose tolerance (Mitchell et al. 2016). ZnT8 is one of four human vesicular zinc transporters. It supplies millimolar zinc concentrations to insulin granules in pancreatic beta-cells, affecting insulin processing, crystallisation, and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc, and channels zinc to the transport site in the transmembrane domain (Parsons et al. 2018). The variant, W325R, in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. The CTDs of the WT and mutant proteins form tetramers which are stabilized by zinc binding and exhibit negligible differences in their secondary structural content and zinc-binding affinities in solution (Ullah et al. 2020). Xue et al. 2020 described cryo-EM structures in both outward- and inward-facing conformations. HsZnT8 forms a dimeric structure with four Zn2+ binding sites within each subunit with a highly conserved primary site in the TMD housing the Zn2+ substrate. An interfacial site between the TMD and the CTD modulates the Zn2+ transport activity. Two adjacent sites buried in the cytosolic domain are chelated by conserved residues from CTD and the His-Cys-His (HCH) motif from the N-terminal segment of the neighboring subunit. A comparison of the outward- and inward-facing structures reveals that the TMD of each subunit undergoes a large structural rearrangement, allowing for alternating access to the primary Zn2+ site during the transport cycle (Xue et al. 2020). The C-terminal domain of the human zinc transporter hZnT8 Is structurally indistinguishable from its disease risk variant (R325W) (Ullah et al. 2020). The dynamics of ZnT8 have been studied (Sala et al. 2021), revealing that packing of the TMSs affects channel accessibility from the cytosol. The dimer interface that keeps the two TM channels in contact became looser in both variants upon zinc binding to the transport site, suggesting that this may be an important step toward the switch from the inward- to the outward-facing states of the protein (Sala et al. 2021). The C-terminal cysteines, which are part of the cytosolic domain, are involved in a metal chelation and/or acquisition mechanism, and provides the first example of metal-thiolate coordination chemistry in zinc transporters (Catapano et al. 2021). Human ZnT8 (SLC30A8) is a diabetes risk factor and a zinc transporter (Daniels et al. 2020). .

Accession Number:Q8IWU4
Protein Name:Zinc transporter 8
Length:369
Molecular Weight:40755.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate

Cross database links:

Entrez Gene ID: 169026   
Pfam: PF01545   
KEGG: hsa:169026    hsa:169026   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0030667 C:secretory granule membrane
GO:0030658 C:transport vesicle membrane
GO:0042803 F:protein homodimerization activity
GO:0008270 F:zinc ion binding
GO:0005385 F:zinc ion transmembrane transporter activity
GO:0030073 P:insulin secretion
GO:0032024 P:positive regulation of insulin secretion
GO:0061088 P:regulation of sequestering of zinc ion
GO:0060627 P:regulation of vesicle-mediated transport
GO:0009749 P:response to glucose stimulus
GO:0032119 P:sequestering of zinc ion
GO:0034341 P:response to interferon-gamma
GO:0070555 P:response to interleukin-1

References (20)

[1] “Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules.”  Chimienti F.et.al.   15331542
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “The full-ORF clone resource of the German cDNA consortium.”  Bechtel S.et.al.   17974005
[4] “DNA sequence and analysis of human chromosome 8.”  Nusbaum C.et.al.   16421571
[5] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[6] “ZnT-8, a pancreatic beta-cell-specific zinc transporter.”  Chimienti F.et.al.   16158222
[7] “In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.”  Chimienti F.et.al.   16984975
[8] “Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese.”  Smidt K.et.al.   17118530
[9] “Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9.”  Overbeck S.et.al.   17971500
[10] “A genome-wide association study identifies novel risk loci for type 2 diabetes.”  Sladek R.et.al.   17293876
[11] “Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules.”  Chimienti F.et.al.   15331542
[12] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[13] “The full-ORF clone resource of the German cDNA consortium.”  Bechtel S.et.al.   17974005
[14] “DNA sequence and analysis of human chromosome 8.”  Nusbaum C.et.al.   16421571
[15] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[16] “ZnT-8, a pancreatic beta-cell-specific zinc transporter.”  Chimienti F.et.al.   16158222
[17] “In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.”  Chimienti F.et.al.   16984975
[18] “Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese.”  Smidt K.et.al.   17118530
[19] “Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9.”  Overbeck S.et.al.   17971500
[20] “A genome-wide association study identifies novel risk loci for type 2 diabetes.”  Sladek R.et.al.   17293876
Structure:
6XPD   6XPE   6XPF     

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FASTA formatted sequence
1:	MEFLERTYLV NDKAAKMYAF TLESVELQQK PVNKDQCPRE RPEELESGGM YHCHSGSKPT 
61:	EKGANEYAYA KWKLCSASAI CFIFMIAEVV GGHIAGSLAV VTDAAHLLID LTSFLLSLFS 
121:	LWLSSKPPSK RLTFGWHRAE ILGALLSILC IWVVTGVLVY LACERLLYPD YQIQATVMII 
181:	VSSCAVAANI VLTVVLHQRC LGHNHKEVQA NASVRAAFVH ALGDLFQSIS VLISALIIYF 
241:	KPEYKIADPI CTFIFSILVL ASTITILKDF SILLMEGVPK SLNYSGVKEL ILAVDGVLSV 
301:	HSLHIWSLTM NQVILSAHVA TAASRDSQVV RREIAKALSK SFTMHSLTIQ MESPVDQDPD 
361:	CLFCEDPCD