3FFN

Crystal structure of calcium-free human gelsolin

Summary for 3FFN

• Entry DOI: 10.2210/pdb3ffn/pdb
• Related: 1D0N 1H1V 1P8X 1P8Z 1RGI 2FGH
• Descriptor: Gelsolin (2 entities in total)
• Functional Keywords: gelsolin, actin, ca-dependent, actin capping, actin-binding, alternative initiation, amyloid, amyloidosis, calcium, cytoplasm, cytoskeleton, disease mutation, disulfide bond, phosphoprotein, polymorphism, secreted, actin binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cytoplasm, cytoskeleton. Isoform 1: Secreted: P06396
• Total number of polymer chains: 2
• Total formula weight: 171596.80

Authors

Chumnarnsilpa, S.,Robinson, R.C.,Burtnick, L.D. (deposition date: 2008-12-04, release date: 2009-10-06, Last modification date: 2024-02-21)

Primary citation

Nag, S.,Ma, Q.,Wang, H.,Chumnarnsilpa, S.,Lee, W.L.,Larsson, M.,Kannan, B.,Hernandez-Valladares, M.,Burtnick, L.D.,Robinson, R.C.
Ca2+ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin.
Proc.Natl.Acad.Sci.USA, 106:13713-13718, 2009

PubMed Abstract: Gelsolin consists of six homologous domains (G1-G6), each containing a conserved Ca-binding site. Occupation of a subset of these sites enables gelsolin to sever and cap actin filaments in a Ca-dependent manner. Here, we present the structures of Ca-free human gelsolin and of Ca-bound human G1-G3 in a complex with actin. These structures closely resemble those determined previously for equine gelsolin. However, the G2 Ca-binding site is occupied in the human G1-G3/actin structure, whereas it is vacant in the equine version. In-depth comparison of the Ca-free and Ca-activated, actin-bound human gelsolin structures suggests G2 and G6 to be cooperative in binding Ca(2+) and responsible for opening the G2-G6 latch to expose the F-actin-binding site on G2. Mutational analysis of the G2 and G6 Ca-binding sites demonstrates their interdependence in maintaining the compact structure in the absence of calcium. Examination of Ca binding by G2 in human G1-G3/actin reveals that the Ca(2+) locks the G2-G3 interface. Thermal denaturation studies of G2-G3 indicate that Ca binding stabilizes this fragment, driving it into the active conformation. The G2 Ca-binding site is mutated in gelsolin from familial amyloidosis (Finnish-type) patients. This disease initially proceeds through protease cleavage of G2, ultimately to produce a fragment that forms amyloid fibrils. The data presented here support a mechanism whereby the loss of Ca binding by G2 prolongs the lifetime of partially activated, intermediate conformations in which the protease cleavage site is exposed.

PubMed: 19666512
DOI: 10.1073/pnas.0812374106

Experimental method

X-RAY DIFFRACTION (3 Å)