The role of s-palmitoylation in neurological diseases: implication for zDHHC family

Abstract

S-palmitoylation is a reversible posttranslational modification, and the palmitoylation reaction in human-derived cells is mediated by the zDHHC family, which is composed of S-acyltransferase enzymes that possess the DHHC (Asp-His-His-Cys) structural domain. zDHHC proteins form an autoacylation intermediate, which then attaches the fatty acid to cysteine a residue in the target protein. zDHHC proteins sublocalize in different neuronal structures and exert dif-ferential effects on neurons. In humans, many zDHHC proteins are closely related to human neu-rological disor-ders. This review focuses on a variety of neurological disorders, such as AD (Alz-heimer's disease), HD (Huntington's disease), SCZ (schizophrenia), XLID (X-linked intellectual disability), attention deficit hyperactivity disorder and glioma. In this paper, we will discuss and summarize the research progress regarding the role of zDHHC proteins in these neu-rological disorders.

Keywords: S-palmitoylation; glutamate receptor; neurological diseases; protein acyltransferase; scaffold protein; zDHHC.

FIGURE 1

The transmembrane domain and conserved sequences of the ZDHHC family. (A) Most ZDHHCs possess 4 TMDs and DHHC-CDR sequences that are located before TMD3. The proteins are mainly distributed in the Golgi, endoplasmic reticulum, and plasma membrane. (B) ZDHHC4 and ZDHHC24 have 5 TMDs, and the DHHC-CDR sequence is located before TMD3. They are mainly found in the Golgi and endoplasmic reticulum. (C) ZDHHC13, ZDHHC17 and ZDHHC23 have 6 TMDs, and the DHHC-CDR se-quence is located before TMD4. They are mainly found in the Golgi, endoplasmic reticulum, and plasma membrane.

FIGURE 2

Tetrahedral coordination environment of zDHHC-CRD. One of the purple spheres carries epitaxial Zn²⁺. Three Cys and one His are bound around the spheres.

FIGURE 3

Structural illustrations of zDHHC-mediated protein palmitoylation. (A) Two-step catalytic mechanism of zDHHC proteins. CoA binds to the cysteines of long-chain fatty acids to form fatty acyl-CoA. The first step of fatty acyl-CoA facilitates the autoacylation of zDHHC at the membrane, which causes fatty acid lipids to bind to sulfhydryl groups in the cysteine-rich region of zDHHC. The second step brings the cysteine-carrying substrate close to the cell membrane, ultimately binding the fatty acid to the substrate protein. (B) Structure of human zDHHC20 palmitoyltransferase, irreversibly inhibited by 2-bromopalmitate. The surface structure of zDHHC20 is gray (PDB entry 6BML (Rana et al., 2018b)), 2-bromopalmitate is colored by element (C-yellow, H-gray, O-red), and the side chains involved in the zDHHC20-CRD catalytic triplex are indicated by small rods and colored by element (C-purple, H-gray, N-blue, O-red, S-yellow). 2-Bromopalmitate irreversibly binds with zDHHC20 and promotes the alkylation of cysteines on DHHC motifs to inhibit autopalmitoylation. (C) The structure of human zDHHC20 (PDB entry 6BML (Rana et al., 2018b)) is indicated in PyMOL. TMD 1-4 is indicated as a green helix. The two zinc ions are represented as grayish purple spheres. Side chains involved in the zDHHC20-CRD catalytic triplex are represented by small rods and colored by element (C-purple, H-gray, N-blue, O-red, S-yellow). (D) The crystal structure of human zDHHS20 bound to palmitoyl coenzyme A [PDB entry 7KHM (Lee et al., 2022)] is indicated by PyMOL. The zDHHC surface structure is gray, palmitoyl coenzyme A is colored by element (C-orange, H-gray, N-blue, O-red, S-yellow), and the fatty acyl chain is inserted into a hydrophobic pocket within the transmembrane region of the protein. The zDHHC20-CRD catalytic triplex involves a side chain indicated by a small bar that is colored by element (C-purple, H-gray, N-blue, O-red, S-yellow). zDHHC binds to palmitoyl coenzyme A, and the cysteine at position 156 becomes a serine.