Section: Research

Kai Lin, Ph.D.

Other Affiliation(s):
   Center for AIDS Research

Structural basis of protein phosphorylation control.

The general interest of my laboratory is to understand how extracellular signals are integrated intracellularly to produce biological responses. Such signal transduction pathways control many important cellular processes such as cell division, differentiation and immune response. Defects of these tightly regulated and highly cooperative signal transduction pathways lead to abnormal cell growth and immune response. We study the structure-function relationship of the proteins involved in these pathways and their mechanisms of action using a combination of x-ray crystallography, biochemistry and molecular biology techniques.

Currently, we focus on the structural basis by which phosphorylation regulates protein functions, and also mechanisms by which the protein targets and protein kinases/phosphatases achieve specific recognition. These studies are of fundamental importance in understanding how signal transduction is controlled. This goal will be approached through studies of two signaling systems: T cell antigen receptor (TCR) signaling and TGF-b receptor signaling.

T cells play critical roles in host immune responses to pathogens. CD45, a transmembrane protein tyrosine phosphatase (PTPase), plays a critical role in TCR signal transduction by regulating the phosphorylation status of a protein tyrosine kinase, lck. CD45 is composed of an extracellular receptor-like domain and an intracellular portion containing two tandemly arranged PTPase domains. The tandem PTPase structure is found in almost all other transmembrane PTPases, yet little is known about the function of this arrangement. In CD45, only the membrane proximal domain has catalytic function, whereas the role of the membrane distal domain has been controversial. We are interested in understanding the structural basis by which CD45 and lck interact to achieve TCR signal regulation.

The signals of TGF-b superfamily molecules are transduced by a set of evolutionarily conserved proteins known as smad, which upon phosphorylation by the TGF-b receptor kinase translocate to the nucleus where they activate transcription. Several smad proteins have been characterized in vertebrates. The current model suggests that smad4 (known as DPC4) plays a central role in signal distribution by associating as heteroligomers with other pathway-specific smad proteins. We are interested in the receptor kinase-smad protein recognition and how smad proteins work to transduce specific signal from cell surface to nucleus.

E-mail: Kaung.Lin@umassmed.edu
Keywords: Protein-DNA recognition, Signal Transduction, Structural Biology, Gene Regulation, Viral Infections and Immunity

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