8.A.114. The Huntington-interacting protein 14 (HIP14) Family

The Huntington-interacting protein 14 (HIP14) is reported to be a palmitoyltransferase required for exocytosis and targeting of the palmitoylated cysteine string protein (CSP) and the SNAP25 protein which are mislocalized in a HIP14 mutant (Ohyama et al., 2007). HIP14 also palmitoylates CSP. HIP14 may be necessary for presynaptic function including neurotransmitter release by regulating the trafficking of CSP to synapses (Ducker et al., 2004; Ohyama et al., 2007; Stowers and Isacoff, 2007; Yanai et al., 2006).

HIP14 is reported to be a divalent cation transporter capable of transporting Mg2+ found only in eukaryotes (Quamme, 2009). It has up to eight N-terminal Ankyrin repeats (residues 25-270) followed by the transmembrane domain (residues 300-560; The zfDHHC domain superfamily).

The reaction proposed for HIP14 in the second paragraph (above) is:

M2+(in) ⇌ M2+(out)

This family belongs to the .



and Quamme GA. (2010). Molecular identification of ancient and modern mammalian magnesium transporters. Am J Physiol Cell Physiol. 298(3):C407-29.

Ducker, C.E., E.M. Stettler, K.J. French, J.J. Upson, and C.D. Smith. (2004). Huntingtin interacting protein 14 is an oncogenic human protein: palmitoyl acyltransferase. Oncogene 23: 9230-9237.

Goytain, A., R.M. Hines, and G.A. Quamme. (2008). Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2+ transport. J. Biol. Chem. 283: 33365-33374.

Hines, R.M., R. Kang, A. Goytain, and G.A. Quamme. (2010). Golgi-specific DHHC zinc finger protein GODZ mediates membrane Ca2+ transport. J. Biol. Chem. 285: 4621-4628.

McMichael, T.M., L. Zhang, M. Chemudupati, J.C. Hach, A.D. Kenney, H.C. Hang, and J.S. Yount. (2017). The palmitoyltransferase ZDHHC20 enhances interferon-induced transmembrane protein 3 (IFITM3) palmitoylation and antiviral activity. J. Biol. Chem. 292: 21517-21526.

Ohyama, T., P. Verstreken, C.V. Ly, T. Rosenmund, A. Rajan, A.C. Tien, C. Haueter, K.L. Schulze, and H.J. Bellen. (2007). Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles. J. Cell Biol. 179: 1481-1496.

Rana, M.S., C.J. Lee, and A. Banerjee. (2018). The molecular mechanism of DHHC protein acyltransferases. Biochem Soc Trans. [Epub: Ahead of Print]

Rana, M.S., P. Kumar, C.J. Lee, R. Verardi, K.R. Rajashankar, and A. Banerjee. (2018). Fatty acyl recognition and transfer by an integral membrane -acyltransferase. Science 359:.

Runkle, K.B., A. Kharbanda, E. Stypulkowski, X.J. Cao, W. Wang, B.A. Garcia, and E.S. Witze. (2016). Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling. Mol. Cell 62: 385-396.

Schäffers, O.J.M., J.G.J. Hoenderop, R.J.M. Bindels, and J.H.F. de Baaij. (2018). The rise and fall of novel renal magnesium transporters. Am. J. Physiol. Renal Physiol 314: F1027-F1033.

Stowers, R.S. and E.Y. Isacoff. (2007). Drosophila huntingtin-interacting protein 14 is a presynaptic protein required for photoreceptor synaptic transmission and expression of the palmitoylated proteins synaptosome-associated protein 25 and cysteine string protein. J. Neurosci. 27: 12874-12883.

Swarthout, J.T., S. Lobo, L. Farh, M.R. Croke, W.K. Greentree, R.J. Deschenes, and M.E. Linder. (2005). DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J. Biol. Chem. 280: 31141-31148.

Yanai, A., K. Huang, R. Kang, R.R. Singaraja, P. Arstikaitis, L. Gan, P.C. Orban, A. Mullard, C.M. Cowan, L.A. Raymond, R.C. Drisdel, W.N. Green, B. Ravikumar, D.C. Rubinsztein, A. El-Husseini, and M.R. Hayden. (2006). Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci 9: 824-831.


TC#NameOrganismal TypeExample

Huntington-interacting Protein 14, HIP14, of 632 aas and 6 or more TMSS.  This protein has been suggested to be a Mg2+ transporter, but the evidence is equivocal (Schäffers et al. 2018).


HIP14 of Homo sapiens (Q8IUH5)


Huntington-interacting Protein 14, HIP14. Eukaryotic divalent cation transporter (Quamme, 2009)


HIP14 of Drosophila melanogaster (Q9VUW9)


Golgi Ca2+ and Mg2+ transporting palmitoyltransferase GodZ (ZDHHC3) (also palmitoylates protein substrates; Hines et al., 2010; Goytain et al., 2008).  Residues 50-233 in this protein show 27% identity to residues 372-539 in 9.B.37.1.1.


ZDHHC3 (GodZ) of Homo sapiens (Q8R173)


S-acyltransferase of 294 aas and 4 TMSs

S-acyltransferase of Volvox carteri


The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for hRAS and nRAS (Swarthout et al. 2005). 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.  Rana et al. 2018 presented crystal structures of two DHHC palmitoyltransferases and a covalent intermediate mimic. The active site resides at the membrane-cytosol interface allow the enzyme to catalyze thioester-exchange using fatty acyl-coenzyme A, explaining why membrane-proximal cysteines are candidates for palmitoylation. The acyl chain binds in a cavity formed by the transmembrane domain. Rana et al. 2018 proposed a mechanism for acyl chain-length selectivity in DHHC enzymes on the basis of cavity mutants with preferences for shorter and longer acyl chains. Protein S-acylation is a reversible lipidic posttranslational modification where a fatty acid chain is covalently linked to cysteine residues by a thioester linkage (Rana et al. 2018).


The ZDHHC9-GOLGA7 complex of Homo sapiens


Palmitoyltransferase ZDHHC20 of 365 aas and 4 TMSs in a 2 + 2 TMS arrangement.  It catalyzes palmitoylation of Cys residues in target proteins (Runkle et al. 2016). It has a preference for acyl-CoA with C16 fatty acid chains but can also utilize acyl-CoA with C14 and C18 fatty acid chains (Rana et al. 2018). It derivatizes the IFITM3 protein (TC# 8.A.58.1.3) which has anti-viral activity and makes physical contact with the V-ATPase in endosomes which is required for the function of this ATPase (McMichael et al. 2017).


Palmitoyltransferase ZDHHC20 of Homo sapiens


Golgi electrogenic, voltage-dependent, Mg2+-transporting palmitoyltransferase, Huntington-interacting protein, HIP14 (ZDHHC13) (Up-regulated with low [Mg2+]; Km =0.8 mM; regulated by autopalmitoylation) (Goytain et al., 2008).


HIP14 of Homo sapiens (Q8IUH4)