BIOGENESIS AND FUNCTIONAL RECONSTITUTION OF HUMAN MDR1

  • Skach, William (PI)

    Project: Research project

    Project Details

    Description

    The mechanisms of biogenesis and intracellular trafficking of complex
    integral transmembrane proteins are diverse, representing a numberous
    variations on common themes. The steps in this process occur at the
    site and time of synthesis, as well as subsequently, in the endoplasmic
    reticulum and beyond. Study of the biogenesis of several integral
    membrane proteins to date has uncovered unexpected features, some of
    which have important implications for structure, topology and function. The human multi-drug resistance P-glycoprotein (MDR-1) serves as an
    ATP-dependent transporter of chemotherapeutic agents out of cells. It
    has been proposed to span the bilayer twelve times and is structurally
    related to a number of other biologically important proteins including
    the cystic fibrosis transmembrane regulator (CFTR) and the hepatocyte
    bile canalicular anion transporter. Yet, little is known about the
    biogenesis and aquisition of functional competence of any member of this
    family of proteins. In the proposed work, MDR1 will be studied as a proptotype of the
    P-glycoprotein family. MDR1 will be expressed in both cell-free and
    whole cell systems and its intracellular trafficking studied. Assays
    will be developed with which to follow its functional maturation and
    determine where and when during its biogenesis functional maturation
    occurs. Through the use of protein chimeras, the sequences responsible
    for MDR1 biogenesis will be dissected and contrasted to topogenic
    sequences from simpler proteins as well as from other members of the
    P-glycoprotein superfamily. From this work a detailed understanding of the steps by which MDR1
    achieves functional competence will emerge. A system will have been
    established by which newly synthesized MDR-1 can be manipulated in hope
    of understanding its physiologic function and altering its pharmacologic
    properties. Moreover, these studies will provide insight into the
    relationship of MDR-1 to other members of the P-glycoprotein
    superfamily.
    StatusFinished
    Effective start/end date7/1/916/30/96

    Funding

    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health

    ASJC

    • Medicine(all)

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