Best matches for Human palmitoyltransferase DHHC:
Fatty acyl recognition and transfer by an integral membrane S-acyltransferase.
Rana MS et al. Science.
(2018)
Human DHHC proteins: a spotlight on the hidden player of palmitoylation.
Korycka J et al. Eur J Cell Biol.
(2012)DHHC
(Asp-His-His-Cys) palmitoyltransferases are eukaryotic integral membrane
enzymes that catalyze protein palmitoylation, which is important in a
range of physiological processes, including small guanosine
triphosphatase (GTPase) signaling, cell adhesion, and neuronal receptor
scaffolding. We present crystal structures of two DHHC
palmitoyltransferases and a covalent intermediate mimic. The active
site resides at the membrane-cytosol interface, which allows the enzyme
to catalyze thioester-exchange chemistry by using fatty acyl-coenzyme A
and explains why membrane-proximal cysteines are candidates for
palmitoylation. The acyl chain binds in a cavity formed by the
transmembrane domain. We propose a mechanism for acyl chain-length
selectivity in DHHC enzymes on the basis of cavity mutants with preferences for shorter and longer acyl chains.
Zinc co-ordination by the DHHC cysteine-rich domain of the palmitoyltransferase Swf1.
González Montoro A et al. Biochem J.
(2013) Abstract
S-acylation,
commonly known as palmitoylation, is a widespread post-translational
modification of proteins that consists of the thioesterification of one
or more cysteine residues with fatty acids. This modification is
catalysed by a family of PATs (palmitoyltransferases), characterized by
the presence of a 50-residue long DHHC-CRD
(Asp-His-His-Cys cysteine-rich domain). To gain knowledge on the
structure-function relationships of these proteins, we carried out a
random-mutagenesis assay designed to uncover essential amino acids in
Swf1, the yeast PAT responsible for the palmitoylation of SNARE (soluble
N-ethylmaleimide-sensitive fusion protein-attachment protein receptor)
proteins. We identified 21 novel loss-of-function mutations, which are
mostly localized within the DHHC-CRD. Modelling of the tertiary structure of the Swf1 DHHC
domain suggests that it could fold as a zinc-finger domain,
co-ordinating two zinc atoms in a CCHC arrangement. All residues
predicted to be involved in the co-ordination of zinc were found to be
essential for Swf1 function in the screen. Moreover, these mutations
result in unstable proteins, in agreement with a structural role for
these zinc fingers. The conservation of amino acids predicted to form
each zinc-binding pocket suggests a shared function, as the selective
pressure to maintain them is lost upon mutation of one of them. A Swf1
orthologue that lacks one of the zinc-binding pockets is able to
complement a yeast swf1∆ strain, possibly because a similar fold can be
stabilized by hydrogen bonds instead of zinc co-ordination. Finally, we
show directly that recombinant Swf1 DHHC-CRD is able to bind zinc. Sequence analyses of DHHC domains allowed us to present models of the zinc-binding properties for all PATs.
1.
Gorinski
N, Wojciechowski D, Guseva D, Abdel Galil D, Mueller FE, Wirth A,
Thiemann S, Zeug A, Schmidt S, Zaręba-Kozioł M, Wlodarczyk J, Skryabin
BV, Glage S, Fischer M, Al-Samir S, Kerkenberg N, Hohoff C, Zhang W,
Endeward V, Ponimaskin E.
J Biol Chem. 2020 Mar 17. pii: jbc.RA119.011049. doi: 10.1074/jbc.RA119.011049. [Epub ahead of print] ....suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.
2.
Ernst AM, Toomre D, Bogan JS.
Front Cell Dev Biol. 2019 Jun 12;7:109. doi: 10.3389/fcell.2019.00109. eCollection 2019. Review.Abstract
The Golgi is well
known to act as center for modification and sorting of proteins for
secretion and delivery to other organelles. A key sorting step occurs at
the trans-Golgi network and is mediated by protein adapters. However, recent data indicate that sorting also occurs much earlier, at the cis-Golgi,
and uses lipid acylation as a novel means to regulate anterograde flux.
Here, we examine an emerging role of S-palmitoylation/acylation as a
mechanism to regulate anterograde routing. We discuss the critical
Golgi-localized DHHC S-palmitoyltransferase
enzymes that orchestrate this lipid modification, as well as their
diverse protein clients (e.g., MAP6, SNAP25, CSP, LAT, β-adrenergic
receptors, GABA receptors, and GLUT4 glucose transporters). Critically,
for integral membrane proteins, S-acylation can act as new a
"self-sorting" signal to concentrate these cargoes in rims of Golgi
cisternae, and to promote their rapid traffic through the Golgi or,
potentially, to bypass the Golgi. We discuss this mechanism and examine
its potential relevance to human physiology and disease, including diabetes and neurodegenerative diseases.
3.
Yang Q, Zheng F, Hu Y, Yang Y, Li Y, Chen G, Wang W, He M, Zhou R, Ma Y, Xu D, Tian X, Gao X, Wang Q, Wang X.
Cell Death Dis. 2018 Jul 23;9(8):795. doi: 10.1038/s41419-018-0842-0.
4.
Kim Y, Yang H, Min JK, Park YJ, Jeong SH, Jang SW, Shim S.
Biochem Biophys Res Commun. 2018 Jan 22;495(4):2573-2578. doi: 10.1016/j.bbrc.2017.12.128. Epub 2017 Dec 26.Similar articles
5.
McMichael TM, Zhang L, Chemudupati M, Hach JC, Kenney AD, Hang HC, Yount JS.
J Biol Chem. 2017 Dec 29;292(52):21517-21526. doi: 10.1074/jbc.M117.800482. Epub 2017 Oct 27.Abstract
Interferon-induced transmembrane
protein 3 (IFITM3) is a cellular endosome- and lysosome-localized
protein that restricts numerous virus infections. IFITM3 is activated by
palmitoylation, a lipid posttranslational modification. Palmitoylation
of proteins is primarily mediated by zinc finger DHHC
domain-containing palmitoyltransferases (ZDHHCs), but which members of
this enzyme family can modify IFITM3 is not known. Here, we screened a
library of human
cell lines individually lacking ZDHHCs 1-24 and found that IFITM3
palmitoylation and its inhibition of influenza virus infection remained
strong in the absence of any single ZDHHC, suggesting functional
redundancy of these enzymes in the IFITM3-mediated antiviral response.
In an overexpression screen with 23 mammalian ZDHHCs, we unexpectedly
observed that more than half of the ZDHHCs were capable of increasing
IFITM3 palmitoylation with ZDHHCs 3, 7, 15, and 20 having the greatest
effect. Among these four enzymes, ZDHHC20 uniquely increased IFITM3
antiviral activity when both proteins were overexpressed. ZDHHC20
colocalized extensively with IFITM3 at lysosomes unlike ZDHHCs 3, 7, and
15, which showed a defined perinuclear localization pattern, suggesting
that the location at which IFITM3 is palmitoylated may influence its
activity. Unlike knock-out of individual ZDHHCs, siRNA-mediated
knockdown of both ZDHHC3 and ZDHHC7 in ZDHHC20 knock-out cells decreased
endogenous IFITM3 palmitoylation. Overall, our results demonstrate that
multiple ZDHHCs can palmitoylate IFITM3 to ensure a robust antiviral
response and that ZDHHC20 may serve as a particularly useful tool for
understanding and enhancing IFITM3 activity.
Free PMC Article
Free PMC Article
6.
Sharma C, Wang HX, Li Q, Knoblich K, Reisenbichler ES, Richardson AL, Hemler ME.
Cancer Res. 2017 Dec 15;77(24):6880-6890. doi: 10.1158/0008-5472.CAN-17-1536. Epub 2017 Oct 20.
- PMID:
- 29055014
7.
Daniotti JL, Pedro MP, Valdez Taubas J.
Traffic. 2017 Nov;18(11):699-710. doi: 10.1111/tra.12510. Epub 2017 Sep 24. Review.
- PMID:
- 28837239
8.
Abrami L, Dallavilla T, Sandoz PA, Demir M, Kunz B, Savoglidis G, Hatzimanikatis V, van der Goot FG.
Elife. 2017 Aug 15;6. pii: e27826. doi: 10.7554/eLife.27826.
- PMID:
- 28826475
9.
Verardi R, Kim JS, Ghirlando R, Banerjee A.
Structure. 2017 Sep 5;25(9):1337-1347.e6. doi: 10.1016/j.str.2017.06.018. Epub 2017 Jul 27.
- PMID:
- 28757145
10.
Mukherjee A, Wang Z, Kinlough CL, Poland PA, Marciszyn AL, Montalbetti N, Carattino MD, Butterworth MB, Kleyman TR, Hughey RP.
J Biol Chem. 2017 Mar 10;292(10):4152-4163. doi: 10.1074/jbc.M117.776146. Epub 2017 Jan 30.
- PMID:
- 28154191
11.
González Montoro A, Chumpen Ramirez S, Valdez Taubas J.
J Biol Chem. 2015 Sep 11;290(37):22448-59. doi: 10.1074/jbc.M115.651356. Epub 2015 Jul 29.
- PMID:
- 26224664
12.
Tian
H, Lu JY, Shao C, Huffman KE, Carstens RM, Larsen JE, Girard L, Liu H,
Rodriguez-Canales J, Frenkel EP, Wistuba II, Minna JD, Hofmann SL.
Mol Cancer Res. 2015 Apr;13(4):784-94. doi: 10.1158/1541-7786.MCR-14-0608. Epub 2015 Jan 8.
- PMID:
- 25573953
13.
Ren W, Sun Y, Du K.
Mol Cell Biol. 2013 Nov;33(21):4255-65. doi: 10.1128/MCB.00527-13. Epub 2013 Sep 3.
- PMID:
- 24001771
14.
González Montoro A, Quiroga R, Valdez Taubas J.
Biochem J. 2013 Sep 15;454(3):427-35. doi: 10.1042/BJ20121693.
- PMID:
- 23790227
15.
Gorleku OA, Barns AM, Prescott GR, Greaves J, Chamberlain LH.
J Biol Chem. 2011 Nov 11;286(45):39573-84. doi: 10.1074/jbc.M111.272369. Epub 2011 Sep 18.
- PMID:
- 21926431
16.
Tian L, McClafferty H, Jeffries O, Shipston MJ.
J Biol Chem. 2010 Jul 30;285(31):23954-62. doi: 10.1074/jbc.M110.137802. Epub 2010 May 27.
- PMID:
- 20507996
17.
Jennings BC, Nadolski MJ, Ling Y, Baker MB, Harrison ML, Deschenes RJ, Linder ME.
J Lipid Res. 2009 Feb;50(2):233-42. doi: 10.1194/jlr.M800270-JLR200. Epub 2008 Sep 30.
- PMID:
- 18827284
18.
McCormick PJ, Dumaresq-Doiron K, Pluviose AS, Pichette V, Tosato G, Lefrancois S.
Traffic. 2008 Nov;9(11):1984-97. doi: 10.1111/j.1600-0854.2008.00814.x. Epub 2008 Aug 9.
- PMID:
- 18817523
19.
Swarthout JT, Lobo S, Farh L, Croke MR, Greentree WK, Deschenes RJ, Linder ME.
J Biol Chem. 2005 Sep 2;280(35):31141-8. Epub 2005 Jul 6.
Covalent lipid modifications mediate the membrane attachment and
biological activity of Ras proteins. All Ras isoforms are farnesylated
and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are
further modified by palmitoylation. Yeast Ras is palmitoylated by the DHHC cysteine-rich domain-containing protein Erf2 in a complex with Erf4. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC
cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein
that has limited sequence similarity to yeast Erf4. DHHC9 and GCP16
co-distribute in the Golgi apparatus, a location consistent with the
site of mammalian Ras palmitoylation in vivo. Like yeast Erf2.Erf4,
DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for
protein fatty acyltransferase activity and protein stability. Purified
DHHC9. GCP16 exhibits substrate specificity, palmitoylating H- and N-Ras
but not myristoylated G (alphai1) or GAP-43, proteins with N-terminal
palmitoylation motifs. Hence, DHHC9. GCP16 displays the properties of a
functional human ortholog of the yeast Ras palmitoyltransferase Free Article
20.
Valdez-Taubas J, Pelham H.
EMBO J. 2005 Jul 20;24(14):2524-32. Epub 2005 Jun 23.Protein palmitoylation is a post-translational modification that affects
a great number of proteins. In most cases, the enzymes responsible for
this modification have not been identified. Some proteins use
palmitoylation to attach themselves to membranes; however,
palmitoylation also occurs in transmembrane proteins, and the function
of this palmitoylation is less clear. Here we identify Swf1, a member of
the DHHC-CDR
family of palmitoyltransferases, as the protein responsible for
modifying the yeast SNAREs Snc1, Syn8 and Tlg1, at cysteine residues
close to the cytoplasmic end of their single transmembrane domains
(TMDs). In an swf1Delta mutant, Tlg1 is mis-sorted to the vacuole. This
occurs because unpalmitoylated Tlg1 is recognised by the ubiquitin
ligase Tul1, resulting in its targeting to the multivesicular body
pathway. Our results suggest that one role of palmitoylation is to
protect TMDs from the cellular quality control machinery, and that Swf1
may be the enzyme responsible for most, if not all, TMD-associated
palmitoylation in yeast.
- PMID:
- 15973437
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