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Lawrence S. Shapiro, PhD

Academic Appointments

  • Professor of Ophthalmic Sciences (in Ophthalmology and in the Naomi Berrie Diabetes Center)
  • Professor of Biochemistry and Molecular Biophysics
Lawrence S. Shapiro, PhD
The lab focuses mainly on the biology of cell adhesion, particularly as it relates to establishing synaptic connections between neurons, using the retina as the primary model system. Research in the lab encompasses both molecular-level studies using X-ray crystallography to understand the structure and function of individual proteins, as well as cellular and histologic studies to understand their roles in vivo. There are two primary projects underway in our laboratory: (1) We are examining the structure, function, and retinal expression of a family of putative neural cell adhesion proteins called protocadherins. These proteins, which are distinct from yet resemble cadherin cell adhesion proteins, are expressed with a remarkable specificity: Neurons of identical lineage in close proximity to each other appear to choose one or a few protocadherins to express (of the 52 in the genome), and this choice differs from one cell to the next. Protocadherins are localized primarily at synapses, suggesting the possibility that their differential adhesion may be important in wiring neural circuits. To investigate this possibility, we have produced specific antibodies to 15 of the 52 protocadherins, and using immunohistochemistry are in the process of correlating the expression of these proteins with the known neural circuits of the retina. (2) We are also investigating the biology of tubby proteins, which we have shown to function as signaling factors downstream from heterotrimeric G-proteins. The tubby mutant mouse exhibits an obesity/insulin-resistance/retinopathy phenotype, and dysfunction of tubby-like protein 1(TULP1) is the cause of retinitis pigmentosa type 14. A collaborator in France has identified a human tubby mutants who exhibit a syndrome similar to that of the tubby mouse. We are now working to understand the biochemical origin of the dysfunction of these mutants.

The nervous system is unique and remarkable in the complexity of the precise interconnections among its component cells. The human brain is composed of roughly ten billion neurons, each of which can participate in thousands of connections. Thus, the genetically-directed assembly of the nervous system involves formation of about 1013 specific interconnections between neurons. Implementation of this extraordinarily precise program depends on the controlled spatial and temporal expression of selective adhesion molecules on neural cell surfaces. Although the full complement of proteins responsible for specific adhesion in the nervous system remains unclear, many families of neural adhesion molecules have been identified and studied in detail. Our focus is on structural studies of neural adhesion molecules to reveal the molecular basis of their function and atomic-level details of their binding specificity.

Much of our efforts are focused on the cadherins, a large family of cell surface proteins that mediate adhesive binding between cells in both vertebrates and invertebrates. Crystal Structures of cadherins show that binding interactions form only between the N-terminal domains of the extracellular regions. The idea that these domains encode cadherin cell adhesive specificity has been verified by structre-based mutagenesis experiments. There are several subfamilies of cadherins expressed in the nervous system, including type I, type II, and protocadherins. The sorting of motor neuron pools is dependent on the unique distributions of type II cadherins expressed by the cells of each motor neuron pool.

Our long-term goal is to determine the atomic-level basis for specific adhesion in a variety of neural systems.

Departmental Appointments

  • Department of Ophthalmology
  • Department of Biochemistry and Molecular Biophysics

Centers/Institutes/Programs

  • Herbert Irving Comprehensive Cancer Center

Lab Locations

Research Interests

  • Synapses and Circuits
  • Axon Pathfinding and Synaptogenesis
  • Biophysics/Ion Channels
  • Cellular/Molecular/Developmental Neuroscience

NIH Grants

  • HIGH RESOLUTION ANALYSES OF ENV-DIRECTED B CELLS TO ACCELERATE VACCINE DESIGN-P2 (Federal Gov)

    Apr 1 2014 - Mar 31 2019

    EVOLUTION OF GLYCAN - REACTIVE BROADLY NEUTRALIZING ANTI-V2 ANTIBODIES IN HIV INFECTION (Federal Gov)

    Aug 1 2014 - Jul 31 2017

    THE STRUCTURAL BASIS OF CIS AND TRANS PROTOCADHERIN INTERACTIONS (Federal Gov)

    Sep 1 2013 - May 31 2017

    MOLECULAR BASIS OF CADHERIN MEDIATED CELL ADHESION (Federal Gov)

    Apr 1 2012 - Jan 31 2017

    FLUORESCENCE METHODS FOR HT VALIDATION AND PRODUCTION OF PROTEIN COMPLEXES (Federal Gov)

    Apr 1 2011 - Mar 31 2016

    NYSBC STRUCTURAL GENOMICS OF MEMBRANE PROTEINS (Federal Gov)

    Jul 1 2010 - Dec 31 2015

    NYSBC STRUCTURAL GENOMICS OF MEMBRANE PROTEINS (Federal Gov)

    Jul 1 2010 - Jun 30 2015

    PROINFLAMMATORY ENZYMES IN AMYTROPHIC LATERAL SCLEROSIS (Federal Gov)

    Aug 1 2001 - Feb 28 2014

    CADHERIN-11 IN CANCER AND RHEUMATOID ARTHRITIS: COMMON TARGET, COMMON THERAPIES (Federal Gov)

    Sep 1 2012 - Jun 30 2013

    STRUCTURAL AND FUNCTIONAL STUDIES OF INVERTEBRATED CLASSICAL CADHERINS (Federal Gov)

    Sep 1 2008 - Aug 31 2012

    STRUCTURE AND MECHANISM OF THE AMP-ACTIVATED PROTEIN KINASE (Federal Gov)

    Aug 1 2009 - Jul 31 2012

    STRUCTURE AND MECHANISM OF THE AMP-ACTIVATED PROTEIN KINASE (Federal Gov)

    Aug 1 2009 - Jul 31 2012

    THERAPEUTIC ANTIBODIES DIRECTED AGAINST CADHERIN-11 (Private)

    Jun 11 2009 - Feb 28 2012

    ADIPONECTIN AND RESISTIN: STRUCTURE, FUNCTION, AND EFFECT (Federal Gov)

    Apr 15 2005 - Mar 31 2009

Publications

  • Chen, C.P., Posy,S., Ben-Shaul, A., Shapiro, L., Honig, B. (2005).Specificity ofcell-cell adhesion by classical cadherins: critical roleforlow-affinity dimerization through beta-strand swapping. PNAS, 102:8531-6
  • Patel,S.D., Chen, C.P., Bahna, F., Honig, B., and Shapiro, L.(2003).Cadherin-mediated cell-cell adhesion: sticking together as afamily.Curr. Opin Struct. Biol., 13: 690-698.
  • Boggon, T.J., Murray, J., Chapuis-Flament, S., and Shapiro, L.(2002).Crystal Structure of the C-cadherin Ectodomain and Implicationsfor theMechanism of Adhesion. Science, 296: 1308-1313.