Allosteric modulation of nucleoporin assemblies by intrinsically disordered regions

Area of Science:

• Structural biology
• Molecular biophysics
• Cell biology

Background:

• Intrinsically disordered regions (IDRs) are crucial for protein interactions in macromolecular assemblies.
• The molecular mechanisms governing IDR function within complex cellular structures are not fully understood.

Purpose of the Study:

• To elucidate the allostery-based mechanism regulating the nuclear pore complex (NPC) soluble core.
• To understand how distinct intrinsically disordered regions (IDRs) in Nup53 mediate interactions with other nucleoporins and karyopherins (Kaps).

Main Methods:

• Integration of thermodynamic and structural data.
• Analysis of protein-protein interactions involving Nup53, Nic96, Nup157, and Kaps.

Main Results:

• Discovery of an allostery-based mechanism controlling the NPC soluble core.
• Identification of functionally coupled IDRs within Nup53 that bind to partner nucleoporins and Kaps.
• Demonstration that the Nup53·Kap121 complex adopts an ensemble of structures, destabilizing Nup53 hub interactions.

Conclusions:

• The study provides a molecular framework for understanding communication between disordered and folded domains in macromolecular complexes.
• Allosteric regulation by IDRs is a key mechanism in nuclear pore complex assembly and function.