Versatile allosteric properties in Pex5-like tetratricopeptide repeat proteins to induce diverse downstream function

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Tetratricopeptide repeat (TPR) proteins are α-solenoid tandem-repeat proteins with conformational flexibility and multi-ligand binding capabilities.
• The peroxisomal import receptor Pex5 uses TPR triplets to recognize the Peroxisomal Targeting Signal (PTS) 1 motif on cargo proteins.
• TRIP8b, a regulator of HCN ion channels, shares a similar TPR architecture and binds to a C-terminal motif analogous to PTS1.

Purpose of the Study:

• To review the overarching role of molecular allostery in the diverse functions of TPR array proteins.
• To highlight the conserved mechanisms of cargo recognition and allosteric coupling in unrelated TPR proteins.
• To propose TPR array proteins as a model for other α-solenoid proteins involved in translocation.

Main Methods:

• Review of existing literature and data on Pex5 and TRIP8b protein structures and functions.
• Comparative analysis of TPR architecture, ligand-binding motifs (PTS1), and N-terminal domains.
• Examination of allosteric mechanisms driving cargo loading, coupling, and functional readouts.

Main Results:

• Pex5 and TRIP8b exhibit similar TPR structures and bind distinct cargos via analogous C-terminal motifs.
• A conserved N-terminal domain in Pex5 and TRIP8b provides a secondary binding site and mediates allosteric coupling.
• Protein import/regulation by TPR proteins is driven by allosteric binding, coupling, and release, independent of external energy.

Conclusions:

• Molecular allostery is a fundamental mechanism driving the diverse functions of TPR array proteins.
• The conserved structural and functional principles in Pex5 and TRIP8b underscore a common evolutionary strategy.
• TPR proteins serve as a valuable model for understanding α-solenoid proteins in membrane translocation processes.