Role of Calcium Binding in Alpha IIb Integrin Biogenesis

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
The platelet integrin alpha-IIb-beta3 mediates platelet aggregation and plays a
critical role in hemostasis. Patients without functional alphaIIb-beta3
receptors manifest in the bleeding disorder Glanzmann thrombasthenia (GT).
The medical importance of alphalIb-beta3 is highlighted, by the ability of
alphalIb-beta3 antagonists to prevent the ischemic complications of unstable
angina and percutaneous coronary interventions. Some mutations in the
alphalIb submit that result in GT have been shown to completely block
maturational processing of alphalIb, causing the protein to be retained in the
endoplasmic reticulum (ER). In particular, mutations in and around the four
cation-binding domains of alpha1Ib universally result in ER retention. These
specific cases of GT comprise a paradigm for agenetic disease caused by a
conformational change in protein structure which results in abnormal ER
processing, and ultimately results in ER retention and degradation. The
alpha1Ib cation-binding domains have highly conserved hydrophobic residues
that are required for the normal biogenesis of the receptor complex. Even
conservative amino acid substitutions in these regions profoundly affects the
level of alpha1Ib expression and degree of maturation. These data suggest
that the conservative changes in the cation-binding domains are altering their
structure, which affects their cation binding affinity. That these changes
result in ERAD suggest that calcium binding to the cation-binding domains is
essential for normal ER processing of alpha1Ib. This hypothesis will be
tested by the following specific aims: (1) To test the hypothesis that normal maturation of the alpha1Ib subunit requires structurally intact cation binding
domains. (2) To test the hypothesis that normal biogenesis of the alpha1Ib-beta3
receptor complex requires calcium binding to the alpha1lb cation-binding
domains. (3) To identify ER chaperones that interact with alpha1Ib, and to
test the hypothesis that calcium binding to the alpha1Ib cation-binding,
affects interaction with chaperone proteins.
StatusFinished
Effective start/end date9/30/027/31/08

ASJC

  • Medicine(all)