Structural Portrait of Filamin Interaction Mechanisms

Abstract

We review the most recent findings on human filamin structure, with particular emphasis on the relationships between structure, function, and interaction. Filamin is a cytoskeletal actin-binding protein and it is therefore crucial in providing cells with the necessary mechanical and dynamical properties. Filamentous actin cross-linking by filamin is regulated by a number of other proteins and the molecular mechanisms of this complex interaction network can be understood by highlighting the structural features of isolated filamin moieties and of their complexes with several partners. Here we describe first the structure-function relationships of the isolated filamin, its flexibility, and its dimerization mechanism. Secondly, we illustrate the structural mechanism with which filamin can recognize its partners, both the actin filaments and the regulatory proteins.

Small-Angle X-Ray Scattering Reveals Compact Domain-Domain Interactions in the N-Terminal Region of Filamin C

“…A comparison of different FLN sequences shows a repeating pattern of two domains, suggesting that the protein has evolved via tandem duplications of two domains [5]. In line with this, a regular pattern of alternating calculated isoelectric points of neighboring domains can be observed in all three vertebrate FLN isoforms [6]. These features correlate with the existence of three closely interacting domain pairs in the Rod 2 region of FLNa: domains 16–17, 18–19 and 20–21 [7], [8].…”

“…Until recently, the Rod 2 region of FLNs has been identified as the major player of the mechanosensor function. On the contrary, the domains in Rod 1 are considered to have an extended domain arrangement [6], [14] and their function is not entirely clear. Studies have been conducted in the past in an attempt to understand the role of Rod 1 domains by comparing their sequences with the Rod 2 domains and then measuring their interactions.…”

RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator

“…PKC isoforms, for example, contain C2 domains, the putative RACK1 partners dynamin and spectrin contain PH domains (49), and NHERF1 contains PDZ domains. Interestingly, C2 domains and FlnA-Ig repeats have similar immunoglobulin-like protein folds, consisting of ␤-sandwiches with large, conformationally variable loops that connect individual ␤-strands (14,48). While the topologies of C2 domains and FlnA-Ig repeats are not equivalent, their structural similarities raise the possibility that they may bind RACK1 in a similar manner.…”

“…These sequences typically contain a linchpin serine residue, flanked by alternating hydrophobic residues. Upon binding, these motifs form ␤-strand-type backbone interactions with the third strand of the Ig-repeat and hydrophobic sidechain packing contacts with the fourth strand (14). The N-terminal cytoplasmic tail of CFTR, among other proteins, interacts with FlnA in this manner (55).…”

“…Repeats Ig1-Ig23 are organized into two extended rod-like domains, consisting, respectively, of Ig1-Ig15 and Ig16-Ig23 (46). Individual Ig repeats, in particular repeats 17,19,21, and 23, interact with unstructured, extended C-or N-terminal motifs in the cytosolic domains of numerous membrane proteins, transporters, channels, and receptors, including CFTR (14,22). Disruption of the CFTR:FlnA interaction specifically affects surface residence times and reduces apical surface expression of CFTR (43,55,58), potentially due to increased endocytosis and inefficient CFTR recycling.…”