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.
In molecular biology theDHHC domain is aprotein domain that acts as anenzyme, which adds apalmitoyl chemical group toproteins in order to anchor them tocell membranes. The DHHC domain was discovered in 1999 and named after a conservedsequence motif found in itsprotein sequence.[1] Roth and colleagues showed that theyeast Akr1p protein couldpalmitoylate Yck2pin 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 asZDHHC3 andZDHHC7 enhance palmitoylation of proteins such asPSD-95,SNAP-25,GAP43,Gαs. Others such asZDHHC9 showed specificity only toward theH-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.
Conserved motifs within protein sequences point towards the most importantamino acid residues for function. In the DHHC domain there is a tetrapeptide motif composed ofaspartate-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-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. ADPG (aspartate-proline-glycine) motif has been identified just to theC-terminus of the secondtransmembrane region.[5] ATTxE (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 anasparagine called the PaCCT motif (PAlmitoiltransferase Conserved C-Terminus motif).[6]
Several structures of the DHHC domain has been solved, and it is known to run on a linearly-arrangedcatalytic triad of Asp153, His154, and Cys156. It runs on aping-pong mechanism, where the cysteine attacks the acyl-CoA to form an S-acylated DHHC, and then the acyl group is transferred to the substrate. DHHR enzymes exist, and they (as well as some DHHC enzymes) may use aternary complex mechanism instead.[7]
In 2006, five chemical classes of small molecules were discovered which were shown to act against palmitoyltransferases.[8]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 to2-Bromopalmitate and were identified as able toinhibit 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.[9] 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.[9]
Several proteins containing DHHC domains have been implicated in human disease. Twomissense mutations within the DHHC domain ofZDHHC9 were identified inX-linkedmental retardation associatedwith aMarfanoid Habitus.[10] A potential link ofZDHHC11 with bladder cancer has been suggested by the discovery that 5 out of 9 high-grade bladder cancer samples surveyed contained aduplication of the 5p15.33 genomic region.[11] However, this region contains another geneTPPP which may be the causative gene. TheHIP14 palmitoyltransferase is responsible for palmitoylating theHuntingtin 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 ofHuntington's disease.[12] A gene knockout experiment of the mouse homologue ofZDHHC13 showed hair loss, severeosteoporosis, and systemicamyloidosis, both ofAL andAA depositions.[13]
^abFukata 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.PMID17012030.
^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.PMID19138168.
^Rana, MS; Lee, CJ; Banerjee, A (28 February 2019). "The molecular mechanism of DHHC protein acyltransferases".Biochemical Society Transactions.47 (1):157–167.doi:10.1042/BST20180429.PMID30559274.S2CID56175691.
^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.PMID2888271.
^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:10.1159/000111132.PMID18025801.S2CID26826882.
Hou H, John Peter AT, Meiringer C, Subramanian K, Ungermann C (August 2009). "Analysis of DHHC acyltransferases implies overlapping substrate specificity and a two-step reaction mechanism".Traffic.10 (8):1061–73.doi:10.1111/j.1600-0854.2009.00925.x.PMID19453970.S2CID38799662.
Ohno Y, Kihara A, Sano T, Igarashi Y (April 2006). "Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins".Biochim. Biophys. Acta.1761 (4):474–83.doi:10.1016/j.bbalip.2006.03.010.hdl:2115/14509.PMID16647879.
Uemura T, Mori H, Mishina M (August 2002). "Isolation and characterization of Golgi apparatus-specific GODZ with the DHHC zinc finger domain".Biochem. Biophys. Res. Commun.296 (2):492–6.doi:10.1016/S0006-291X(02)00900-2.PMID12163046.
