Abstract
Cortactin is a filamentous actin-binding protein that plays a pivotal role in translating environmental signals into coordinated rearrangement of the cytoskeleton. The dynamic reorganization of actin in the cytoskeleton drives processes including changes in cell morphology, cell migration, and phagocytosis. In general, structural proteins of the cytoskeleton bind in the N-terminal region of cortactin and regulatory proteins in the C-terminal region. Previous structural studies have reported an extended conformation for cortactin. It is therefore unclear how cortactin facilitates cross-talk between structural proteins and their regulators. In the study presented here, circular dichroism, chemical cross-linking, and small angle x-ray scattering are used to demonstrate that cortactin adopts a globular conformation, thereby bringing distant parts of the molecule into close proximity. In addition, the actin bundling activity of cortactin is characterized, showing that fully polymerized actin filaments are bundled into sheet-like structures. We present a low resolution structure that suggests how the various domains of cortactin interact to coordinate its array of binding partners at sites of actin branching.
Highlights
Regulated polymerization, depolymerization, and branching of actin filaments drives fundamental cellular mechanical processes such as cell migration, morphology changes, endocytosis, and metastasis
Cortactin Adopts a Globular Conformation in Solution— small angle x-ray scattering (SAXS) data were collected to determine the morphology of cortactin in solution
We used CD spectroscopy to determine the secondary structure composition of cortactin and showed that this protein contains a high percentage of random coil
Summary
Structural studies are key to understanding the molecular basis of cortactin regulation of f-actin branching and rearrangement. Two such studies have been reported previously. The first study used deep-etch electron microscopy and analytical ultracentrifugation to show that cortactin was a “thread-like” molecule, 220 –290 Å long and ϳ20 Å wide [2], consistent with an unstructured “beads-on-a-string” arrangement of the cortactin domains. This structure contributed to a model where cortactin acts as a scaffolding protein. We show that cortactin plays an active role in f-actin morphology by bundling assembled actin filaments into sheets
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