Abstract
The gelsolin family of proteins is a major class of actin regulatory proteins that sever, cap, and nucleate actin filaments in a calcium-dependent manner and are involved in various cellular processes. Typically, gelsolin-related proteins have three or six repeats of gelsolin-like (G) domain, and each domain plays a distinct role in severing, capping, and nucleation. The Caenorhabditis elegans gelsolin-like protein-1 (gsnl-1) gene encodes an unconventional gelsolin-related protein with four G domains. Sequence alignment suggests that GSNL-1 lacks two G domains that are equivalent to fourth and fifth G domains of gelsolin. In vitro, GSNL-1 severed actin filaments and capped the barbed end in a calcium-dependent manner. However, unlike gelsolin, GSNL-1 remained bound to the side of F-actin with a submicromolar affinity and did not nucleate actin polymerization, although it bound to G-actin with high affinity. These results indicate that GSNL-1 is a novel member of the gelsolin family of actin regulatory proteins and provide new insight into functional diversity and evolution of gelsolin-related proteins.
Highlights
The actin cytoskeleton is highly differentiated into sarcomeric structures in striated muscle, and polymerization and depolymerization of actin must be precisely regulated in order to assemble and maintain striated myofibrils
One notable difference between gelsolin and GSNL-1 was that gelsolin has a flexible linker of ϳ50 amino acids between G3 and G4 that acts like a hinge during calcium activation [38], whereas GSNL-1 has only a very short linker of ϳ10 amino acids between G3 and G4 (Fig. 1B), suggesting that gelsolin and GSNL-1 undergo different conformational changes upon calcium activation
Despite the fact that GSNL-1 has an unconventional number of G domains, we predicted that GSNL-1 has an ability to fragment actin filaments, because GSNL-1 has similar sequences to gelsolin in a region of G1 and a linker between G1 and G2 that is crucial for severing (Fig. 1B) [37]
Summary
The actin cytoskeleton is highly differentiated into sarcomeric structures in striated muscle, and polymerization and depolymerization of actin must be precisely regulated in order to assemble and maintain striated myofibrils. Gelsolin strongly severs actin filaments, caps the barbed ends and nucleates actin polymerization in a calcium-dependent manner [17,18,19]. Our biochemical analysis indicates that GSNL-1 is a novel gelsolin-like actin severing and capping protein but, unlike gelsolin, stays bound to the side of actin filaments, binds to G-actin in a 1:1 molar ratio, and does not nucleate actin polymerization.
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