Protein flexibility, not disorder, is intrinsic to molecular recognition

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Intrinsically disordered proteins (IDPs) are typically considered unfolded and functional in this state.
• This view is challenged by the observation that many purified proteins appear disordered in vitro.
• Cellular environments and protein-protein interactions suggest a different model for protein behavior.

Purpose of the Study:

• To re-evaluate the concept of intrinsically disordered proteins.
• To propose that most IDPs are 'proteins waiting for a partner' (PWPs) within multi-component complexes.
• To differentiate between intrinsic protein flexibility and true disorder.

Main Methods:

• Analysis of existing literature and structural data (e.g., X-ray crystallography).
• Comparison of protein behavior in vitro versus in the cellular environment.
• Consideration of mechanisms for protein-protein recognition and complex assembly.

Main Results:

• Flexibility, not disorder, is an intrinsic property of proteins, supported by structural data of enzymes and complexes.
• Observed disorder in purified proteins or crystals may be confused with flexibility.
• True disorder is incompatible with specific protein recognition in the crowded cellular milieu.

Conclusions:

• Most IDPs are likely PWPs, requiring partners for proper folding and function.
• Protein disorder in the cell is likely transient and regulated by chaperones and quality control.
• This reframes our understanding of protein structure, function, and cellular assembly.