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0  structures 347  species 0  interactions 4432  sequences 126  architectures

Family: zf-DHHC (PF01529)

Summary: DHHC palmitoyltransferase

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DHHC domain Edit Wikipedia article

DHHC domain
DHHC topology.png
A depiction of the topology of DHHC family palmitoyltransferases. Transmembrane alpha helices are represented as black tubes. The DHHC domain is shown as a light orange oval.
Identifiers
Symbol DHHC
Pfam PF01529
InterPro IPR001594
PROSITE PDOC50216

In molecular biology the DHHC domain is a protein domain that acts as an enzyme, which adds a palmitoyl chemical group to proteins in order to anchor them to cell membranes. The DHHC domain was discovered in 1999 and named after a conserved sequence motif found in its protein sequence.[1] Roth and colleagues showed that the yeast Akr1p protein could palmitoylate Yck2p in vitro and inferred that the DHHC domain defined a large family of palmitoyltransferases.[2] In mammals twenty three members of this family have been identified and their substrate specificities investigated.[3] Some members of the family such as ZDHHC3 and ZDHHC7 enhance palmitoylation of proteins such as PSD-95, SNAP-25, GAP43, Gαs. Others such as ZDHHC9 showed specificity only toward the H-Ras protein.[3] However, a recent study questions the involvement of classical enzyme-substrate recognition and specificity in the palmitoylation reaction.[4] Several members of the family have been implicated in human diseases.

Sequence motifs[edit]

Conserved motifs within protein sequences point towards the most important amino acid residues for function. In the DHHC domain there is a tetrapeptide motif composed of aspartate-histidine-histidine-cysteine. However this short sequence is embedded in a larger region of about fifty amino acids in length that shares many more conserved amino acids. The canonical DHHC domain can be described with the following sequence motif:

C-x2-C-x9-HC-x2-C-x4-DHHC-x5-C-x4-N-x3-F (x shows region of unconserved residues)

However many examples of DHHC domains are known that do not contain all these conserved residues. In addition to the central DHHC domain three further sequence motifs have been identified in members of the DHHC family. A DPG (aspartate-proline-glycine) motif has been identified just to the C-terminus of the second transmembrane region.[5] A TTxE (threonine-threonine-any-glutamate) motif has also been identified after the fourth transmembrane helix.[5] A third motif towards the C-terminus of many proteins has been identified that contains a conserved aromatic amino acid, a glycine and an asparagine called the PaCCT motif (PAlmitoiltransferase Conserved C-Terminus motif).[6]

Chemical inhibitors[edit]

In 2006, five chemical classes of small molecules were discovered which were shown to act against palmitoyltransferases.[7] Further studies in 2009 showed that of the 5 classes studied, 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one was shown to behave similarly to 2-Bromopalmitate and were identified as able to inhibit the palmitoylation reaction of a range of DHHC domain containing proteins. Inhibition with 2-Bromopalmitate was found to be irreversible, the other however was found to be mostly reversible.[8] Because of the roles of DHHC domain proteins in human diseases it has been suggested that chemical inhibitors of specific DHHC proteins may be a potential route to treatment of disease.[8]

In human disease[edit]

Several proteins containing DHHC domains have been implicated in human disease. Two missense mutations within the DHHC domain of ZDHHC9 were identified in X-linked mental retardation associated with a Marfanoid Habitus.[9] A potential link of ZDHHC11 with bladder cancer has been suggested by the discovery that 5 out of 9 high-grade bladder cancer samples surveyed contained a duplication of the 5p15.33 genomic region.[10] However, this region contains another gene TPPP which may be the causative gene. The HIP14 palmitoyltransferase is responsible for palmitoylating the Huntingtin protein. Expansions of the triplet repeat in the huntington's gene leads to loss of interaction with HIP14 which Yanai and colleagues speculate is involved in the pathology of Huntington's disease.[11] A gene knockout experiment of the mouse homologue of ZDHHC13 showed hair loss, severe osteoporosis, and systemic amyloidosis, both of AL and AA depositions.[12]

Human proteins containing this domain[edit]

ZDHHC1; ZDHHC2; ZDHHC3; ZDHHC4; ZDHHC5; ZDHHC6; ZDHHC7; ZDHHC8; ZDHHC9; ZDHHC11; ZDHHC11B; ZDHHC12; ZDHHC13; ZDHHC14; ZDHHC15; ZDHHC16; ZDHHC17; ZDHHC18; ZDHHC19; ZDHHC20; ZDHHC21; ZDHHC22; ZDHHC23; ZDHHC24;

See also[edit]

References[edit]

  1. ^ Putilina T, Wong P, Gentleman S (May 1999). "The DHHC domain: a new highly conserved cysteine-rich motif". Mol. Cell. Biochem. 195 (1–2): 219–26. doi:10.1023/A:1006932522197. PMID 10395086. 
  2. ^ Roth AF, Feng Y, Chen L, Davis NG (October 2002). "The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase". J. Cell Biol. 159 (1): 23–8. doi:10.1083/jcb.200206120. PMC 2173492. PMID 12370247. 
  3. ^ a b Fukata Y, Iwanaga T, Fukata M (October 2006). "Systematic screening for palmitoyl transferase activity of the DHHC protein family in mammalian cells". Methods 40 (2): 177–82. doi:10.1016/j.ymeth.2006.05.015. PMID 17012030. 
  4. ^ Rocks O, Gerauer M, Vartak N, et al. (April 2010). "The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins". Cell 141 (3): 458–71. doi:10.1016/j.cell.2010.04.007. PMID 20416930. 
  5. ^ a b Mitchell DA, Vasudevan A, Linder ME, Deschenes RJ (June 2006). "Protein palmitoylation by a family of DHHC protein S-acyltransferases". J. Lipid Res. 47 (6): 1118–27. doi:10.1194/jlr.R600007-JLR200. PMID 16582420. 
  6. ^ González Montoro A, Quiroga R, Maccioni HJ, Valdez Taubas J (April 2009). "A novel motif at the C-terminus of palmitoyltransferases is essential for Swf1 and Pfa3 function in vivo". Biochem. J. 419 (2): 301–8. doi:10.1042/BJ20080921. PMID 19138168. 
  7. ^ Stober R (June 1987). "[Total or subtotal amputation of a long finger with destruction of the metacarpophalangeal joint--regaining function by replantation?]". Aktuelle Traumatol (in German) 17 (3): 100–4. PMID 2888271. 
  8. ^ a b Jennings BC, Nadolski MJ, Ling Y, et al. (February 2009). "2-Bromopalmitate and 2-(2-hydroxy-5-nitro-benzylidene)-benzobthiophen-3-one inhibit DHHC-mediated palmitoylation in vitro". J. Lipid Res. 50 (2): 233–42. doi:10.1194/jlr.M800270-JLR200. PMC 2636914. PMID 18827284. 
  9. ^ Raymond FL, Tarpey PS, Edkins S, et al. (May 2007). "Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus". Am. J. Hum. Genet. 80 (5): 982–7. doi:10.1086/513609. PMC 1852737. PMID 17436253. 
  10. ^ Yamamoto Y, Chochi Y, Matsuyama H, et al. (2007). "Gain of 5p15.33 is associated with progression of bladder cancer". Oncology 72 (1–2): 132–8. doi:10.1159/111132. PMID 18025801. 
  11. ^ Yanai A, Huang K, Kang R, et al. (June 2006). "Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function". Nat. Neurosci. 9 (6): 824–31. doi:10.1038/nn1702. PMC 2279235. PMID 16699508. 
  12. ^ Saleem AN, Chen YH, Baek HJ, et al. (2010). "Mice with Alopecia, Osteoporosis, and Systemic Amyloidosis Due to Mutation in Zdhhc13, a Gene Coding for Palmitoyl Acyltransferase". In MacDonald, Marcy E. PLoS Genet. 6 (6): e1000985. doi:10.1371/journal.pgen.1000985. PMC 2883605. PMID 20548961. 

External links[edit]

Further reading[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

DHHC palmitoyltransferase Provide feedback

This family includes the well known DHHC zinc binding domain as well as three of the four conserved transmembrane regions found in this family of palmitoyltransferase enzymes.

Literature references

  1. Mesilaty-Gross S, Reich A, Motro B, Wides R; , Gene 1999;231:173-186.: The drosophila STAM gene homolog is in a tight gene cluster, and its expression correlates to that of the adjacent gene ial. PUBMED:10231582 EPMC:10231582

  2. Boehm S, Frishman D, Mewes HW; , Nucleic Acids Res 1997;25:2464-2469.: Variations of the C2H2 zinc finger motif in the yeast genome and classification of yeast zinc finger proteins. PUBMED:9171100 EPMC:9171100

  3. Putilina T, Wong P, Gentleman S; , Mol Cell Biochem 1999;195:219-226.: The DHHC domain: a new highly conserved cysteine-rich motif. PUBMED:10395086 EPMC:10395086

  4. Bartels DJ, Mitchell DA, Dong X, Deschenes RJ; , Mol Cell Biol 1999;19:6775-6787.: Erf2, a Novel Gene Product That Affects the Localization and Palmitoylation of Ras2 in Saccharomyces cerevisiae. PUBMED:10490616 EPMC:10490616

  5. Lobo S, Greentree WK, Linder ME, Deschenes RJ; , J Biol Chem 2002;277:41268-41273.: Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. PUBMED:12193598 EPMC:12193598


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001594

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 the DHHC-type zinc finger domain, which is also known as NEW1 [PUBMED:10231582]. The DHHC Zn-finger was first isolated in the Drosophila putative transcription factor DNZ1 and was named after a conserved sequence motif [PUBMED:10231582]. This domain has palmitoyltransferase activity; this post-translational modification attaches the C16 saturated fatty acid palmitate via a thioester linkage, predominantly to cysteine residues [PUBMED:17051234]. This domain is found in the DHHC proteins which are palmitoyl transferases [PUBMED:15603741]; the DHHC motif is found within a cysteine-rich domain which is thought to contain the catalytic site.

More information about these proteins can be found at Protein of the Month: Zinc Fingers [PUBMED:].

Gene Ontology

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Domain organisation

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Alignments

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(82)
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RP35
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  Seed
(97)
Full
(4432)
Representative proteomes NCBI
(4268)
Meta
(82)
RP15
(1087)
RP35
(1605)
RP55
(2335)
RP75
(2951)
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  Seed
(97)
Full
(4432)
Representative proteomes NCBI
(4268)
Meta
(82)
RP15
(1087)
RP35
(1605)
RP55
(2335)
RP75
(2951)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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Curation and family details

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Seed source: Pfam-B_945 (release 4.0)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 97
Number in full: 4432
Average length of the domain: 169.10 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 40.72 %

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 21.1 21.1
Trusted cut-off 21.1 21.2
Noise cut-off 21.0 21.0
Model length: 174
Family (HMM) version: 15
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