2017
DOI: 10.7554/elife.27826
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Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade

Abstract: S-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC palmitoyltransferase family is still limited. Here we show that human ZDHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, ZDHHC16, revealing the first palmitoylation cascade. The combination of site specific mutagenesis of the three ZDHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modell… Show more

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Cited by 104 publications
(136 citation statements)
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References 55 publications
(94 reference statements)
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“…Another question, given that high ZDHHC expression is a negative prognostic marker in several cancers (Table ), is to understand biochemically how high ZDHHC enzyme expression promotes tumorigenesis. Experimental and modeling studies indicate that proteins are rarely fully palmitoylated at all possible sites and that ZDHHC overexpression can enhance substrate palmitoylation . Thus, one possibility is that ZDHHC overexpression could produce populations of more fully palmitoylated substrate proteins that exhibit enhanced (oncogenic) activity.…”
Section: Discussionmentioning
confidence: 99%
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“…Another question, given that high ZDHHC expression is a negative prognostic marker in several cancers (Table ), is to understand biochemically how high ZDHHC enzyme expression promotes tumorigenesis. Experimental and modeling studies indicate that proteins are rarely fully palmitoylated at all possible sites and that ZDHHC overexpression can enhance substrate palmitoylation . Thus, one possibility is that ZDHHC overexpression could produce populations of more fully palmitoylated substrate proteins that exhibit enhanced (oncogenic) activity.…”
Section: Discussionmentioning
confidence: 99%
“…Palmitoylated proteins are often substrates for more than one ZDHHC enzyme, but one particular ZDHHC enzyme often has a stronger effect than others on substrate palmitoylation in the cell (e.g. ). Chimeric ZDHHC proteins and structure–function studies have defined specific regions of individual ZDHHC enzymes that promote substrate interaction and palmitoylation, indicating that unique substrate‐binding preferences could guide the palmitoylation of certain proteins .…”
Section: Protein S‐palmitoylation: Basic Biochemical Mechanismsmentioning
confidence: 99%
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“…We do not want to conclude that each of the identified ZDHHCs actually transfers fatty acids to HA. It is possible that they are part of a palmitoylation cascade, similar to the one involved in acylation of ER-resident protein folding factors [54]. In that case, ZDHHC6 catalyzes fatty acid transfer to the protein substrate, but its activity is regulated by ZDHHC16-catalyzed palmitoylation of three cytoplasmic cysteines in ZDHHC6.…”
Section: Zdhhc2 8 15 and 20 Are Involved In Acylation Of Ha And M2 mentioning
confidence: 99%
“…The function of palmitoylation at these sites is unknown but we hypothesise that they may regulate DHHC5 localisation and/or stability. Indeed, recent work has established an important role for palmitoylation of the C-terminus of DHHC6 by DHHC16 in the regulation of its activity and turnover (Abrami et al, 2017). This region of DHHC5 is also involved in substrate recruitment; DHHC5 binds to and palmitoylates the sodium pump regulator phospholemman and this is dependent on a region of the Cterminus of DHHC5 just after its fourth transmembrane domain (Howie et al, 2014).…”
Section: Introductionmentioning
confidence: 99%