Structure/Function Studies of Ser/Thr and Tyr Protein Phosphorylation in Mycobacterium tuberculosis

Abstract

Many bacterial species express ‘eukaryotic-like’ Ser/Thr or Tyr protein kinases and phosphatases that are candidate mediators of developmental changes and host/pathogen interactions. The biological functions of these systems are largely unknown. Recent genetic, biochemical and structural studies have begun to establish a framework for understanding the systems for Ser/Thr and Tyr protein phosphorylation in Mycobacterium tuberculosis (Mtb). Ser/Thr protein kinases (STPKs) appear to regulate diverse processes including cell division and molecular transport. Proposed protein substrates of the STPKs include putative regulatory proteins, as well as six proteins containing Forkhead-associated domains. Structures of domains of receptor STPKs and all three Mtb Ser/Thr or Tyr phosphatases afford an initial description of the principal modules that mediate bacterial STPK signaling. These studies revealed that universal mechanisms of regulation and substrate recognition govern the functions of prokaryotic and eukaryotic STPKs. Several structures also support novel mechanisms of regulation, including dimerization of STPKs, metal-ion binding to PstP and substrate mimicry in PtpB.