BIOC 212 Lecture Notes - Lecture 32: Fibrin, Chondrocyte, Collagen
29 May 2018
School
Department
Course
Professor
Cell Junctions & Cell Adhesion XII
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Integrin Activation --Inside Out
• PM with alpha IIb and b3 integrin on the top left
o Looking at intracellular portion; do not see extracellular portion
o Very short in both cases
• Hallmark is salt bridge between aspartic acid and basic amino acid
o Keep subunits together in inactive conformation
o Positive & negative charges interact with each other
o Non-covalent interaction
• Two activating mechanisms inside the cell, both relying on long extended protein
Talin
o Usually folded back, in inactive conformation
o Head domain (purple) binds to other parts of the protein
• Calpain protease can cleave the head domain off talin (becomes liberated)
o Talin head then binds to beta subunit
• Purple line at the top shows talin binding region
o Pushes salt bridge apart, resulting in same type of conformational change
between two subunits
• Move apart, and get activation
• Other principle, talin interacts with PIP2 (phosphoinositol-4,5 bisphosphate)
o Localized to membrane
o Opens up closed structure of talin, making head domain available to bind to
the beta subunit
• Entire tail protein in this case, but molecular consequences are the same
o Same result again; binding, separation of subunits & activation
Integrins in Activation --Integrin Clustering
• Velcro; analog to integrins
o Low to moderate affinity interactions with extracellular ligands
• Cadherins & integrins
o But when cluster them, increase apparent affinity (avidity)
• Clustering very important
• Affinity: a term used to describe to strength of a single bond
• Avidity describes the combined strength of multiple bond interactions
o Avidity is distinct from affinity
o Avidity is the combined synergistic strength of binding affinities rather than
the sum of bonds
• Affinities of integrins
Document Summary
9 - 10-11: more moderate affinity for extracellular ligands, when bind, re-distribute laterally into clusters. Cell-matrix interactions are dynamic processes: cho cell on fibronectin, paxillin (red, a-actinin (green, 50 minutes (15 s /frame) Integrin alpha knockouts and known human defects: phenotypes of knockout mice, genes for the beta subunits & all but 4 of the alpha subunits have been knocked out, each phenotype is distinct, different roles of various integrins. Integrins play important roles in most biological processes: human mutations in these genes lead to disease, a6b4: epidermolysis bullosa (skin blistering, aiibb3: glanzmann thrombasthenia. Fibronectin --master organizer of ecm: fibronectin is a ecm protein, master organizer of ecm. Integrins play a role in that: assemble into fiber-like structure outside the cell, which in turn helps other matrix proteins to form fibers. Interacts with collagen, heparin, fibrin, proteoglycans: general adhesion protein that anchors cell to matrix, and to act as first molecule deposited to the matrix.
