C9 POLYMERIZATION AND CYTOLYSIS

  • Podack, Eckhard R, (PI)

Project: Research project

Description

C9 polymerization has been recognized as the reaction in complement
essential for the formation of ultrastructural membrane lesions and
cytolysis. In accord with the central role of C9 polymerization during
membrane attack, it is proposed to embark on a detailed investigation of
the molecular mechanism of C5b-8 mediated C9 polymerization. C5b-8 is the
natural C9-polymerizing unit and the elucidation of its mode of action on
C9 may enable us to manipulate C9 polymerization in such a way that it may
become useful for immunotherapeutic purposes. C5b-8 mediated C9
polymerization will be studied by analyzing the reaction of the first C9
molecule with C5b-8 and determining C9's association partner, conformation,
and covalent or noncovalent modification. The primary structure of C9 (and
of C7) will be determined by isolating and sequencing C9 (and C7) cDNA
clones. The domain structure of C9 and poly C9 will be determined by
generating proteolytic fragments of C9, raising antibodies agaist them, and
localizing their binding to poly C9. Determination of the primary and
domain structure of C9 may enable us to use certain peptide segments of C9
alone or together with domains of C5b-8 as cytolytic effector molecules. C9 polymerization by C5b-8 is under the control of soluble and membrane
bound inhibitors. S-protein is the soluble poly C9 inhibitor of plasma.
The membrane bound inhibitor(s) on human erythrocyte membranes will be
isolated and characterized and its cellular distribution determined. The
physiological role of membrane bound poly C9 inhibitors in the protection
of "self" against immunological attack and in the escape of tumor cells
from immune destruction will be assessed.
StatusFinished
Effective start/end date6/1/845/31/90

Funding

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

Fingerprint

Polymerization
Membranes
Protein S
Conformations
complement C5b-8 complex
Tumors
Association reactions
Plasmas
Peptides
Molecules
complement C9 polymer
Antibodies

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)