Factors VIII and V swap fatty feet

Abstract

Factors VIII and V swap fatty feet -------------------------------------- ------------------------------------------------------------------------In this issue of Blood, Gilbert and colleagues present an elegant study on the membrane-interactive domains of factors VIII (FVIII) and V (FV). 1 The 3-dimensional structure of these domains exposes a few characteristic loops, referred to as "fatty feet," which mediate the interaction with lipid membranes. These are similar, but not identical in FVIII and FV. Swapping feet between FV and FVIII resulted in remarkable changes in lipid binding and biologic activity. These data help in understanding how these cofactors assemble with their catalytic partners in the coagulation cascade.

Membrane Interaction of the Factor VIIIa Discoidin Domains in Atomistic Detail

“…1A); eight anti-parallel β-strands are arranged in two major β-sheets, wrapped to form the barrel and then flattened to a sandwich-like shape 11 . Connecting the β-strands at the bottom of the barrel are four hairpin loops also called the spikes (S1-S4, Fig 1A) or fatty feet 12 , the latter designation being due to the presence of multiple solvent exposed hydrophobic residues. These spikes are of particular importance for platelet membrane-aided functionalities because S1-S4 are hypothesized to be inserted into the hydrophobic core of the phospholipid membrane 7,13 .…”

“…For this reason, much attention has been dedicated in the literature (e.g. by alanine mutagenesis 14 , motif mutagenesis 15 and loop-swaps 12 ) to elucidate how affinity and specificity of the FVIIIa molecule (and FVIII C2 on its own) toward phospholipid membranes is controlled by the residues in these spikes. The primary membrane-anchoring domain of FVIIIa is conventionally thought to be the C2 domain 16 .…”

“…The structural topology of the C1 and C2 domains is that of lectin and commonly known as a jellyroll β-barrel (Figure A); eight antiparallel β-strands are arranged in two major β-sheets, wrapped to form the barrel and then flattened to a sandwichlike shape . Connecting the β-strands at the bottom of the barrel are four hairpin loops also called the spikes [S1–S4 (Figure A)] or fatty feet, the latter designation being due to the presence of multiple solvent-exposed hydrophobic residues. These spikes are of particular importance for platelet membrane-aided functionalities because S1–S4 are hypothesized to be inserted into the hydrophobic core of the phospholipid membrane. , For this reason, much attention has been dedicated in the literature (e.g., by alanine mutagenesis, motif mutagenesis, and loop swaps) to elucidate how the affinity and specificity of the FVIIIa molecule (and FVIII C2 on its own) toward phospholipid membranes are controlled by the residues in these spikes.…”

“…Connecting the β-strands at the bottom of the barrel are four hairpin loops also called the spikes [S1–S4 (Figure A)] or fatty feet, the latter designation being due to the presence of multiple solvent-exposed hydrophobic residues. These spikes are of particular importance for platelet membrane-aided functionalities because S1–S4 are hypothesized to be inserted into the hydrophobic core of the phospholipid membrane. , For this reason, much attention has been dedicated in the literature (e.g., by alanine mutagenesis, motif mutagenesis, and loop swaps) to elucidate how the affinity and specificity of the FVIIIa molecule (and FVIII C2 on its own) toward phospholipid membranes are controlled by the residues in these spikes. The primary membrane-anchoring domain of FVIIIa is conventionally thought to be the C2 domain .…”

Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches

“…Curiously, there is nontrivial interplay and cooperation between the domains in determining the precise binding kinetics and lipid component specificity for the full-length cofactors. 82 83 84 The structures of FV and FVIII C2 domains were solved by X-ray crystallography 85 86 as an eight-stranded Greek-key topology β-barrel with moderately long hairpins, or spikes (or “fatty feet” 87 ) at the bottom (the opposite side of N- and C-terminal ends). These spikes include hydrophobic residues toward the tips, and it is suggested that C2 domains bind to membrane surfaces facilitated by these spikes, while a few other strategically placed basic residues interact with anionic headgroups of the membrane lipids, yielding Ca 2+ -independent stereospecific recognition toward PS lipids.…”