The structural architecture of MRL proteins

The enhanced motility of malignant tumor cells supports their invasion of surrounding tissue. Preventing the spread of cancer cells has become an important therapeutic approach for treating a variety of cancers. Recently, cell motility and actin dynamics have been found to associate with a group of adapter signaling proteins, designated the MRL family (based on family members MIG-10/RIAM/Lamellipodin). MRL proteins contain an RA-PH structural unit. This structural unit is responsible for both Ras GTPase binding and membrane localization of MRL. In part based on these interaction properties, these proteins are recognized as an important convergence point that links upstream signaling with actin dynamics.

RIAM and lamellipodin, the mammalian members of the MRL group, were shown to regulate cell migration by

Molecular mechanisms governing the regulation of cell migration

 interacting with the Ena/VASP proteins. We are interested in investigating the structural basis of the recruitment of MRL proteins to the Ena/VASP actin-binding proteins. The EVH1 domain of Ena/VASP binds specifically to the FP4 motifs in RIAM and lamellipodin. Previous study reveals that the RA-PH structural unit of MRL proteins may oligomerize through the amino terminal coiled-coil region. Our ongoing work indicates that the MRL proteins may function in clustering actin filaments that are bound to the Ena/VASP tetramer, thereby resulting in polymerization of actin filaments at the leading edge of the lamellipodium.  

It has been shown that RIAM, a mammalian member of the MRL family, mediates integrin-induced cell adhesion by recruiting talin to the plasma membrane. Despite high structural similarity, however, a second MRL protein, lamellipodin, lacks the ability to activate integrin-induced cell adhesion, possibly due to a different GTPase binding specificity, or alternatively, because of differences in its ability to interact with talin. Prior to integrin binding, talin adopts an autoinhibitory conformation by masking the integrin-interacting domain by a C-terminal 5-helical bundle domain in the cytoplasm. Our interest is to use X-ray crystallography as an approach to understanding the structural basis of how RIAM binding disrupts this autoinhibitory conformation of talin.