The Intrinsic Relationship between Structure and Function of the Sialyltransferase ST8Sia Family Members.

The Intrinsic Relationship between Structure and Function of the Sialyltransferase ST8Sia Family Members.

Curr Top Med Chem. 2017 Apr 14;:

Authors: Huang RB, Cheng D, Lu B, Liao SM, Troy Ii FA, Zhou GP

Abstract
As a subset of glycosyltransferases, the family of sialyltransferases catalyze transfer of sialic acid (Sia) residues to terminal non-reducing positions on oligosaccharide chains of glycoproteins and glycolipids, utilizing CMP-Neu5Ac as the activated sugar nucleotide donor. In the four known sialyltransferase families (ST3Gal, ST6Gal, ST6GalNAc and ST8Sia), the ST8Sia family catalyzes synthesis of si,8-linked sialic/polysialic acid (polySia) chains according to their acceptor specificity. We have determined 3D structural models of the ST8Sia family members, designated ST8Sia I(1), II(2), IV(4), V(5), and VI(6) using the Phyre2 server. Accuracy of these predicted models are based on the ST8Sia III crystal structure as the calculated template. The common structural features of these models are: (1) Their parallel aemplats and disulfide bonds are buried within the enzymes and are predominately surrounded by helices; (2) The anti-parallel β-sheets are located at the N-terminal region of the enzymes; (3) The mono-sialytransferases (mono-STs), ST8Sia I and VI, contain only a singly pair of disulfide bonds, and there are no anti-parallel -sheets in ST8Sia VI; (4) The N-terminal region of all of the mono-STs are located some distant away from their core structure; (5) These conformational features show that the 3D structures of the mono-STs are less tightly packed than the two polySTs, ST8Sia II and IV, and the oligo-ST, ST8Sia III. These structural features relate to the catalytic specificity of the monoST; (6) In contrast, the tighter structural features of ST8Sia II, IV and III relate to their ability to catalyze the processive synthesis of oligo- (ST8Sia III) and polySia chains (ST8Sia II & IV); (7) Although ST8Sia II, III and IV have similar conformations in their corresponding polysialyltransferase domain (PSTD) and polybasic region (PBR) motifs, the structure of ST8Sia III is looser than that of ST8Sia II and IV, and the amino acid components of the several three-residue-loops in these two motifs of ST8Sia III are different from that in ST8Sia II and IV. This is likely the structural basis for why ST8Sia III is an oligoST and not able to polysialylate and; (8) In contrast, essentially all amino acids within the three-residue-loops in the PSTD of ST8Sia II and IV are highly conserved, and many amino acids in the loops and the helices of these two motifs are critical for NCAM polysialylation by mutational analysis and confirmed by our recent NMR results. In summary, these new findings provide further insights into the molecular mechanisms underlying polySTs-NCAM recognition, polySTs-polySA/oligoSA interactions, and polysialylation of NCAM.

PMID: 28413949 [PubMed - as supplied by publisher]

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