Two distinct mechanisms for actin capping protein regulation--steric and allosteric inhibition.

PLoS Biology
Shuichi TakedaYasushi Nitanai

Abstract

The actin capping protein (CP) tightly binds to the barbed end of actin filaments, thus playing a key role in actin-based lamellipodial dynamics. V-1 and CARMIL proteins directly bind to CP and inhibit the filament capping activity of CP. V-1 completely inhibits CP from interacting with the barbed end, whereas CARMIL proteins act on the barbed end-bound CP and facilitate its dissociation from the filament (called uncapping activity). Previous studies have revealed the striking functional differences between the two regulators. However, the molecular mechanisms describing how these proteins inhibit CP remains poorly understood. Here we present the crystal structures of CP complexed with V-1 and with peptides derived from the CP-binding motif of CARMIL proteins (CARMIL, CD2AP, and CKIP-1). V-1 directly interacts with the primary actin binding surface of CP, the C-terminal region of the alpha-subunit. Unexpectedly, the structures clearly revealed the conformational flexibility of CP, which can be attributed to a twisting movement between the two domains. CARMIL peptides in an extended conformation interact simultaneously with the two CP domains. In contrast to V-1, the peptides do not directly compete with the barbed end for the b...Continue Reading

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Methods Mentioned

BETA
X-ray
surface plasmon resonance
circular dichroism
chip
pull-down
gel filtration
PCR
protein folding

Software Mentioned

Refmac
Molrep
CARMIL
Coot
HKL2000
Bia
evaluation
CNS
ClustalW

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