Crystal structure of Lamellipodin implicates diverse functions in actin polymerization and Ras signaling.
10.1007/s13238-013-2082-5
- Author:
Yu-Chung CHANG
1
;
Hao ZHANG
;
Mark L BRENNAN
;
Jinhua WU
Author Information
1. Department of Developmental Therapeutics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
- Publication Type:Journal Article
- MeSH:
Actins;
metabolism;
Amino Acid Sequence;
Binding Sites;
Carrier Proteins;
chemistry;
genetics;
metabolism;
Crystallography, X-Ray;
Humans;
Membrane Proteins;
chemistry;
genetics;
metabolism;
Molecular Sequence Data;
Mutagenesis;
Phosphatidylinositols;
metabolism;
Polymerization;
Protein Binding;
Protein Structure, Tertiary;
Recombinant Proteins;
biosynthesis;
chemistry;
genetics;
Signal Transduction;
ras Proteins;
metabolism
- From:
Protein & Cell
2013;4(3):211-219
- CountryChina
- Language:English
-
Abstract:
The adapter protein Lamellipodin (Lpd) plays an important role in cell migration. In particular, Lpd mediates lamellipodia formation by regulating actin dynamics via interacting with Ena/VASP proteins. Its RA-PH tandem domain configuration suggests that like its paralog RIAM, Lpd may also mediate particular Ras GTPase signaling. We determined the crystal structures of the Lpd RA-PH domains alone and with an N-terminal coiled-coil region (cc-RA-PH). These structures reveal that apart from the anticipated coiled-coil interaction, Lpd may also oligomerize through a second intermolecular contact site. We then validated both oligomerization interfaces in solution by mutagenesis. A fluorescence-polarization study demonstrated that Lpd binds phosphoinositol with low affinity. Based on our crystallographic and biochemical data, we propose that Lpd and RIAM serve diverse functions: Lpd plays a predominant role in regulating actin polymerization, and its function in mediating Ras GTPase signaling is largely suppressed compared to RIAM.
