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David Lambright, Ph.D.Academic Role: Professor
Faculty Appointment(s) In:
Joint Faculty In:
Other Affiliation(s):
Structural and molecular mechanisms of cell signaling and membrane trafficking
Rab GTPases comprise a large family of molecular switches that function in membrane trafficking and organelle biogenesis by cycling between active (GTP bound) and inactive (GDP bound) states. Activation is regulated by guanine nucleotide exchange factors (GEFs), which promote exchange of GTP for GDP in response to extracellular or intracellular signals. Inactivation is regulated by GTPase-activating proteins (GAPs), which stimulate the hydrolysis of GTP. In the active state, Rab GTPases interact with a diverse effector proteins to regulate vesicle budding, cargo sorting, and motor-dependent transport as well as the tethering, docking, and fusion of vesicles with target membranes. We seek to understand the structural basis underlying the nucleotide dependent interactions of Rab GTPases with effectors and regulatory factors and determine the mechanisms by which these interactions regulate membrane trafficking. Towards this end, we have developed a novel structural proteomic strategy to profile interactions with the Rab family and determine the underlying structural bases. High throughput microplate assays are used to quantitatively profile interactions with GEFs, effectors, and GAPs. In addition to identifying novel interaction partners, the family-wide analyses facilitate crystallographic studies of Rab-GEF, Rab-effector, and Rab-GAP complexes and are also being used to characterize interactions of Rab GTPases with viral and bacterial virulence factors. Lipid second messengers known as phosphoinositides regulate a broad spectrum of cellular functions including survival, membrane trafficking, cytoskeletal dynamics, and migration. Targets of phosphoinositides include pleckstrin homology (PH) and FYVE domains in modular signaling and trafficking proteins. Our goal is to understand how phosphoinositide binding domains recognize phosphoinositides and elucidate the mechanisms by which phosphoinositides regulate the assembly and activation of multiprotein signaling and trafficking complexes on intracellular membranes. A third area of interest concerns an evolutionarily conserved protein, Zpr1, which is required for viability, normal cell cycle progression, and cell growth. Zpr1 is retained in the cytoplasm of quiescent cells through interactions with inactive growth factor receptors and, following stimulation, assembles into cytoplasmic complexes with elongation factor 1-alpha (eEF1A) and nuclear complexes with the survival motor neurons (SMN) protein. An exon deletion in the SMN1 gene that disrupts the interaction with Zpr1 is responsible for the most severe form of spinal muscular atrophy known as Werdnig-Hoffmann syndrome. We have solved the crystal structure of Zpr1 and are working on the structural bases underlying the interactions with growth factor receptors, EF1A, and the SMN complex.
Office: Suite 115 Biotech II
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Research in this laboratory is concerned with structural and molecular mechanisms of cell signaling and membrane trafficking. Our approach combines a broad range of experimental methods from diverse disciplines including biochemistry, biophysics, X-ray crystallography, and bioinformatics as well as molecular, cell, and systems biology. Areas of interest include the regulation of membrane trafficking by Rab GTPases, phosphoinositide signaling, and the regulation of cell proliferation. Defects in these fundamental regulatory mechanisms play critical roles in complex disease states such as cancer and diabetes as well as genetically linked disorders.
55 Lake Avenue North Worcester, MA 01655