Training in structural biology & glycobiology

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Project Summary Bacterial adhesion and colonization are crucial for bacterial fitness and virulence. Despite the great progress has been made in understanding of this critical biological process, molecular details are largely unknown. Our pioneer studies of a streptococcal fimbriae-associated protein (Fap1) in a model organism, Streptococcus parasanguinis have revealed a new family of bacterial adhesins, serine-rich repeat glycoproteins (SRRPs). This family of proteins is synthesized by a gene cluster coding for glycosyltransferaes and accessory secretion proteins; they are highly conserved in pathogenic streptococci and staphylococci, and play important roles in bacterial interaction with the host cells and pathogenesis. Genetic and biochemical studies have led us to conclude that glycosylation of Fap1 is initiated by a two enzyme heterodimeric complex that is composed by two putative glycosyltransferases Gtf1 and Gtf2. The Gtf complex catalyzes the transfer of GlcNAc to the serine-rich sites of Fap1. Dr. Wu will use his sabbatical leave to obtain training in structural biology and glycobiology to further explore molecular details regarding biogenesis of SRRPs. The proposed training will take place in Imperial College London in Dr. Steve Matthews and Dr. Anne Dell¿s laboratories. Drs. Matthews and Dell are the leading experts in their field, and very interested in Dr. Wu¿s research area and have already collaborated with Dr. Wu in the past on different research projects. Training in their laboratories would allow the PI have better understanding of structural biology and glycobiology, and help the PI apply this state of art research approaches in his current research and develop new research programs which explore functional contribution of SRRPs to pathogenic streptococci and staphylococci. The PI¿s long-term goals are to determine how biogenesis of SRRPs contributes to bacterial virulence and how we can harness the new pathway to design therapeutics. Specific Aim 1: Obtain training in structural biology by solving 3-D high resolution structure of glycosyltransferases that are involved in glycosylation of SRRPs. Dr. Wu will spend 3-4 months on this specific aim. Specific Aim 2: Obtain training in glycobiology by charactering glycan structures attached to SRRPs. Dr. Wu will spend 3-4 months on this specific aim. As SRRPs are highly conserved in pathogenic streptococci and staphylococci, deciphering the molecular events that modulates their biogenesis will not only help us to understand biology of the plaque formation in the oral cavity but also provide new information useful for the design of novel therapeutic targets towards bacterial infections mediated by SRRPs, a new research direction for the PI.