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Structural Research of S-acyltransferases

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S-acyltransferase-catalyzed S-palmitoylation of dynamic proteins is one of the fundamental post-translational modifications involved in a wide range of cellular processes and is implicated in human disease-related issues, immune response regulation, and tumor suppression. In recent years, human S-acyltransferases have been recognized as promising drug targets for cancer therapy.

Progress in structural research of DHHC protein S-acyltransferases

The discovery of the DHHC family of S-acyltransferases is one of the breakthroughs in the field of S-acylation. The DHHC proteins contain a conserved protein structural domain of 51 amino acids, which comprises the Asp-His-His-Cys motif embedded in a cysteine-rich structural domain (CRD). Yeast Erf2 and Akr1 represent the core membrane topology. The structures indicate that the DHHC proteins have at least four transmembrane domains (TMDs) with N-terminal and C-terminal exposures to the cytoplasm. Akr1 and its parallel Akr2 homolog expand at the N-terminal end into multiple anchor protein repeats and two additional TMDs. The structures also include a 16-amino acid acyltransferase-conserved c-terminus (PaCCT).

Analysis of the S-acyltransferase mechanism of action

Research on yeast Erf2/Erf4 and mammalian DHHC2/DHHC3 has shown that DHHC proteins have a two-step catalytic mechanism. First, the enzyme undergoes self-acylation using palmitoyl coenzyme a as a donor to form an acylase intermediate. Second, palmitate is transferred to the substrate protein. Mutations in the cysteine in the DHHC motif block both auto-acylation and transfer activity, and mutations in the first histidine block the second step of palmitate transfer. The single transformation supports the hypothesis that DHHC autonylation represents a transient acyl-enzyme transfer intermediate of the two-step ping-pong mechanism. Mass spectrometry analysis of purified DHHC3 confirmed that the DHHC cysteine is modified by palmitate and is the site of the acyl-enzyme intermediate.

Structure of DHHC-PATs. Figure 1. Structure of DHHC-PATs. (Stix R, et al., 2020)

Protein Organism Method Resolution PDB Entry ID
Palmitoyltransferase Danio rerio X-ray diffraction 2.441 Å 6BMS
DHHC20 palmitoyltransferase, space group P63 Homo sapiens X-ray diffraction 2.25 Å 6BMN
DHHC20 palmitoyltransferase, irreversibly inhibited by 2-bromopalmitate Homo sapiens X-ray diffraction 2.95 Å 6BML
Monomeric atSPT-ORM1 (LCB2a-deltaN5) complex Arabidopsis thaliana Cryo-EM single particle analysis 2.8 Å 7YJO
Dimeric atSPT-ORM1 complex Arabidopsis thaliana Cryo-EM single particle analysis 3.2 Å 7YJK
Monomeric atSPT-ORM1 complex Arabidopsis thaliana Cryo-EM single particle analysis 3.2 Å 7YJM
Monomeric atSPT-ORM1 (ORM1-N17A) complex Arabidopsis thaliana Cryo-EM single particle analysis 3.4 Å 7YJN
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa Homo sapiens Cryo-EM single particle analysis 3.3 Å 7K0I
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa protomer Homo sapiens Cryo-EM single particle analysis 3.1 Å 7K0J
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa, 3KS-bound Homo sapiens Cryo-EM single particle analysis 2.6 Å 7K0K
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa, myriocin-bound Homo sapiens Cryo-EM single particle analysis 3.4 Å 7K0L
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa/ORMDL3, class 1 Homo sapiens Cryo-EM single particle analysis 2.9 Å 7K0M
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa/ORMDL3, class 2 Homo sapiens Cryo-EM single particle analysis 3.1 Å 7K0N
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa/ORMDL3, class 3 Homo sapiens Cryo-EM single particle analysis 3.1 Å 7K0O
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa/ORMDL3, class 4 Homo sapiens Cryo-EM single particle analysis 3.1 Å 7K0P
Serine palmitoyltransferase complex SPTLC1/SPLTC2/ssSPTa/ORMDL3, myriocin-bound Homo sapiens Cryo-EM single particle analysis 3.3 Å 7K0Q
Dimeric SPT-ORMDL3 complex Homo sapiens Cryo-EM single particle analysis 3.8 Å 6M4N
Monomeric SPT-ORMDL3 complex Homo sapiens Cryo-EM single particle analysis 3.4 Å 6M4O
Substrate-bound SPT-ORMDL3 complex Homo sapiens Cryo-EM single particle analysis 3.2 Å 7CQI
Substrate-bound SPT-ORMDL3 complex Homo sapiens Cryo-EM single particle analysis 3.3 Å 7CQK
C6-ceramide-bound SPT-ORMDL3 complex Homo sapiens Cryo-EM single particle analysis 2.9 Å 7YIU
SPT-ORMDL3 (ORMDL3-deltaN2) complex Homo sapiens Cryo-EM single particle analysis 3.1 Å 7YJ1
SPT-ORMDL3 (ORMDL3-N13A) complex Homo sapiens Cryo-EM single particle analysis 2.9 Å 7YJ2

Table 1. Structural research of S-acyltransferases.

Creative Biostructure, as a leader in structural analysis, understands the essential importance of obtaining high-quality, reliable structural information for protein function research. Our experienced scientists, state-of-the-art cutting-edge equipment, and proven track record of success make us the ideal partner to satisfy your structural biology requirements.

Our X-ray crystallography and cryo-electron microscopy (cryo-EM) technologies enable in-depth structural and mechanism of action investigations of S-acyltransferases to advance the understanding of their structure and function. and action mechanisms to advance the development of S-acyltransferases in cancer therapy. If you are interested in learning more about our services and how we can help you achieve your goals, please feel free to contact us.

References

  1. Stix R, et al. Structure and Mechanism of DHHC Protein Acyltransferases. J Mol Biol. 2020. 432(18): 4983-4998.
  2. Gottlieb CD, Linder ME. Structure and function of DHHC protein S-acyltransferases. Biochem Soc Trans. 2017. 45(4): 923-928.
  3. Zmuda F, Chamberlain LH. Regulatory effects of post-translational modifications on zDHHC S-acyltransferases. J Biol Chem. 2020. 295(43): 14640-14652.

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