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19  structures 529  species 0  interactions 15070  sequences 495  architectures

Family: zf-RING_2 (PF13639)

Summary: Ring finger domain

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RING finger domain Edit Wikipedia article

Zinc finger, C3HC4 type (RING finger)
1chc animated.gif
Structure of the C3HC4 domain.[1] Zinc ions are black spheres, coordinated by cysteines residues (blue).
Identifiers
Symbol zf-C3HC4
Pfam PF00097
InterPro IPR001841
SMART SM00184
PROSITE PDOC00449
SCOP 1chc
SUPERFAMILY 1chc

In molecular biology, a RING (Really Interesting New Gene) finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations.[2][3][4][5] This protein domain contains from 40 to 60 amino acids. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

Zinc fingers[edit]

Zinc finger (Znf) domains are relatively small protein motifs that bind one or more zinc atoms, and which usually contain multiple finger-like protrusions that make tandem contacts with their target molecule. They bind DNA, RNA, protein and/or lipid substrates.[6][7][8][9][10] Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing.[11] Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

Some Zn finger domains have diverged such that they still maintain their core structure, but have lost their ability to bind zinc, using other means such as salt bridges or binding to other metals to stabilise the finger-like folds.

Function[edit]

Many RING finger domains simultaneously bind ubiquitination enzymes and their substrates and hence function as ligases. Ubiquitination in turn targets the substrate protein for degradation.[12][13][14]

Structure[edit]

The RING finger domain has the consensus sequence C-X2-C-X[9-39]-C-X[1-3]-H-X[2-3]-C-X2-C-X[4-48]-C-X2-C.[2] where:

  • C is a conserved cysteine residue involved zinc coordination,
  • H is a conserved histidine involved in zinc coordination,
  • Zn is zinc atom, and
  • X is any amino acid residue.

The following is a schematic representation of the structure of the RING finger domain:[2]

                              x x x     x x x
                             x      x x      x
                            x       x x       x
                           x        x x        x
                          C        C   C        C
                         x  \    / x   x \    /  x
                         x    Zn   x   x   Zn    x
                          C /    \ H   C /    \ C
                          x         x x         x
                 x x x x x x         x         x x x x x x

Examples[edit]

Examples of human genes which encode proteins containing a RING finger domain include:

AMFR, BBAP, BFAR, BIRC2, BIRC3, BIRC7, BIRC8, BMI1, BRAP, BRCA1, CBL, CBLB, CBLC, CBLL1, CHFR, COMMD3, DTX1, DTX2, DTX3, DTX3L, DTX4, DZIP3, HCGV, HLTF, HOIL-1, IRF2BP2, KIAA1542, LNX1, LNX2, LOC51136, LONRF1, LONRF2, LONRF3, MARCH1, MARCH10, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6, MARCH7, MARCH8, MARCH9, MEX3A, MEX3B, MEX3C, MEX3D, MGRN1, MIB1, MID1, MID2, MKRN1, MKRN2, MKRN3, MKRN4, MNAT1, MYLIP, NFX1, NFX2, PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, PCGF6, PDZRN3, PDZRN4, PEX10, PJA1, PJA2, PML, PML-RAR, PXMP3, RAD18, RAG1, RAPSN, RBCK1, RBX1, RC3H1, RC3H2, RCHY1, RFP2, RFPL1, RFPL2, RFPL3, RFPL4B, RFWD2, RFWD3, RING1, RNF2, RNF4, RNF5, RNF6, RNF7, RNF8, RNF10, RNF11, RNF12, RNF13, RNF14, RNF19A, RNF20, RNF24, RNF25, RNF26, RNF32, RNF38, RNF39, RNF40, RNF41, RNF43, RNF44, RNF55, RNF71, RNF103, RNF111, RNF113A, RNF113B, RNF121, RNF122, RNF123, RNF125, RNF126, RNF128, RNF130, RNF133, RNF135, RNF138, RNF139, RNF141, RNF144A, RNF145, RNF146, RNF148, RNF149, RNF150, RNF151, RNF152, RNF157, RNF165, RNF166, RNF167, RNF168, RNF169, RNF170, RNF175, RNF180, RNF181, RNF182, RNF185, RNF207, RNF213, RNF215, SH3MD4, SH3RF1, SH3RF2, SYVN1, TIF1, TMEM118, TOPORS, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRAF7, TRAIP, TRIM2, TRIM3, TRIM4, TRIM5, TRIM6, TRIM7, TRIM8, TRIM9, TRIM10, TRIM11, TRIM13, TRIM15, TRIM17, TRIM21, TRIM22, TRIM23, TRIM24, TRIM25, TRIM26, TRIM27, TRIM28, TRIM31, TRIM32, TRIM34, TRIM35, TRIM36, TRIM38, TRIM39, TRIM40, TRIM41, TRIM42, TRIM43, TRIM45, TRIM46, TRIM47, TRIM48, TRIM49, TRIM50, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58, TRIM59, TRIM60, TRIM61, TRIM62, TRIM63, TRIM65, TRIM67, TRIM68, TRIM69, TRIM71, TRIM72, TRIM73, TRIM74, TRIML1, TTC3, UHRF1, UHRF2, VPS11, VPS8, ZNF179, ZNF294, ZNF313, ZNF364, ZNF650, ZNFB7, ZNRF1, ZNRF2, ZNRF3, ZNRF4, and ZSWIM2.

References[edit]

  1. ^ Barlow PN, Luisi B, Milner A, Elliott M, Everett R (March 1994). "Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger". J. Mol. Biol. 237 (2): 201–11. doi:10.1006/jmbi.1994.1222. PMID 8126734. 
  2. ^ a b c Borden KL, Freemont PS (1996). "The RING finger domain: a recent example of a sequence-structure family". Curr. Opin. Struct. Biol. 6 (3): 395–401. doi:10.1016/S0959-440X(96)80060-1. PMID 8804826. 
  3. ^ Hanson IM, Poustka A, Trowsdale J (1991). "New genes in the class II region of the human major histocompatibility complex". Genomics 10 (2): 417–24. doi:10.1016/0888-7543(91)90327-B. PMID 1906426. 
  4. ^ Freemont PS, Hanson IM, Trowsdale J (1991). "A novel cysteine-rich sequence motif". Cell 64 (3): 483–4. doi:10.1016/0092-8674(91)90229-R. PMID 1991318. 
  5. ^ Lovering R, Hanson IM, Borden KL, Martin S, O'Reilly NJ, Evan GI, Rahman D, Pappin DJ, Trowsdale J, Freemont PS (1993). "Identification and preliminary characterization of a protein motif related to the zinc finger". Proc. Natl. Acad. Sci. U.S.A. 90 (6): 2112–6. doi:10.1073/pnas.90.6.2112. PMC 46035. PMID 7681583. 
  6. ^ Klug A (1999). "Zinc finger peptides for the regulation of gene expression". J. Mol. Biol. 293 (2): 215–8. doi:10.1006/jmbi.1999.3007. PMID 10529348. 
  7. ^ Hall TM (2005). "Multiple modes of RNA recognition by zinc finger proteins". Curr. Opin. Struct. Biol. 15 (3): 367–73. doi:10.1016/j.sbi.2005.04.004. PMID 15963892. 
  8. ^ Brown RS (2005). "Zinc finger proteins: getting a grip on RNA". Curr. Opin. Struct. Biol. 15 (1): 94–8. doi:10.1016/j.sbi.2005.01.006. PMID 15718139. 
  9. ^ Gamsjaeger R, Liew CK, Loughlin FE, Crossley M, Mackay JP (2007). "Sticky fingers: zinc-fingers as protein-recognition motifs". Trends Biochem. Sci. 32 (2): 63–70. doi:10.1016/j.tibs.2006.12.007. PMID 17210253. 
  10. ^ Matthews JM, Sunde M (2002). "Zinc fingers--folds for many occasions". IUBMB Life 54 (6): 351–5. doi:10.1080/15216540216035. PMID 12665246. 
  11. ^ Laity JH, Lee BM, Wright PE (2001). "Zinc finger proteins: new insights into structural and functional diversity". Curr. Opin. Struct. Biol. 11 (1): 39–46. doi:10.1016/S0959-440X(00)00167-6. PMID 11179890. 
  12. ^ Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM (1999). "RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11364–9. doi:10.1073/pnas.96.20.11364. PMC 18039. PMID 10500182. 
  13. ^ Joazeiro CA, Weissman AM (2000). "RING finger proteins: mediators of ubiquitin ligase activity". Cell 102 (5): 549–52. doi:10.1016/S0092-8674(00)00077-5. PMID 11007473. 
  14. ^ Freemont PS (2000). "RING for destruction?". Curr. Biol. 10 (2): R84–7. doi:10.1016/S0960-9822(00)00287-6. PMID 10662664. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR001841

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This tab holds annotation information from the InterPro database.

InterPro entry IPR001841

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [PUBMED:10529348, PUBMED:15963892, PUBMED:15718139, PUBMED:17210253, PUBMED:12665246]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few [PUBMED:11179890]. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents RING-type zinc finger domains. The RING-finger is a specialised type of Zn-finger of 40 to 60 residues that binds two atoms of zinc, and is probably involved in mediating protein-protein interactions [PUBMED:8317827, PUBMED:8804826, PUBMED:8744354]. There are two different variants, the C3HC4-type and a C3H2C3-type, which are clearly related despite the different cysteine/histidine pattern. The latter type is sometimes referred to as 'RING-H2 finger'. The RING domain is a protein interaction domain that has been implicated in a range of diverse biological processes. E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain. E3 ubiquitin-protein ligases determine the substrate specificity for ubiquitylation and have been classified into HECT and RING-finger families. More recently, however, U-box proteins, which contain a domain (the U box) of about 70 amino acids that is conserved from yeast to humans, have been identified as a new type of E3 [PUBMED:12944364]. Various RING fingers also exhibit binding to E2 ubiquitin-conjugating enzymes (Ubc's) [PUBMED:10662664, PUBMED:10514377, PUBMED:10577187].

Several 3D-structures for RING-fingers are known [PUBMED:8804826, PUBMED:8744354]. The 3D structure of the zinc ligation system is unique to the RING domain and is referred to as the 'cross-brace' motif. The spacing of the cysteines in such a domain is C-x(2)-C-x(9 to 39)-C-x(1 to 3)-H-x(2 to 3)-C-x(2)-C-x(4 to 48)-C-x(2)-C. Metal ligand pairs one and three co-ordinate to bind one zinc ion, whilst pairs two and four bind the second.

Note that in the older literature, some RING-fingers are denoted as LIM-domains. The LIM-domain Zn-finger is a fundamentally different family, albeit with similar Cys-spacing (see INTERPRO).

Gene Ontology

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Domain organisation

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Alignments

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(329)
Full
(15070)
Representative proteomes NCBI
(21355)
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(1292)
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(3177)
RP35
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  Seed
(329)
Full
(15070)
Representative proteomes NCBI
(21355)
Meta
(1292)
RP15
(3177)
RP35
(5561)
RP55
(7989)
RP75
(10132)
Alignment:
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  Seed
(329)
Full
(15070)
Representative proteomes NCBI
(21355)
Meta
(1292)
RP15
(3177)
RP35
(5561)
RP55
(7989)
RP75
(10132)
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Pfam alignments:

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Seed source: Jackhmmer:Q5A9Y7
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 329
Number in full: 15070
Average length of the domain: 45.90 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 10.07 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.0 27.0
Noise cut-off 26.9 26.9
Model length: 44
Family (HMM) version: 1
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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the zf-RING_2 domain has been found. There are 19 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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