Secretory quality control constrains functional selection-associated protein structure innovation.

Area of Science:

• Biophysics
• Molecular Biology
• Evolutionary Biology

Background:

• Biophysical models indicate structural constraints significantly influence protein evolution.
• Protein expression levels and structure-dependent activities dictate in vivo functions.
• Selection often favors structural properties like foldability and stability.

Purpose of the Study:

• To investigate the conserved in vivo functions of C-reactive protein (CRP) despite significant interspecies differences in its expression levels.
• To explore the mechanisms underlying the apparent mismatch between CRP levels and function.
• To determine if conserved native structure or alternative conformations drive CRP's conserved functions.

Main Methods:

• Comparative analysis of C-reactive protein (CRP) levels and functions across different species.
• Investigation of structure-associated activities of both native and unfolded CRP conformations.
• Examination of the role of folding determinants in mediating functional selection and secretion quality control.

Main Results:

• C-reactive protein (CRP) exhibits conserved in vivo functions across species, irrespective of up to two orders of magnitude differences in its expression levels.
• The conserved functions are not attributable to the native structure but are linked to hidden activities of the unfolded, activated CRP conformation.
• Functional selection is mediated by folding determinants, ensuring a stable carrier structure for secretion, rather than direct selection on structural constraints like foldability.

Conclusions:

• A level-function mismatch in C-reactive protein (CRP) evolution is explained by selection acting on hidden activities of its unfolded state, coupled with stringent secretion quality control.
• Folding determinants play a crucial role in maintaining protein structure for secretion, influencing functional selection.
• A folding threshold model may offer insights into the relationship between protein sequence, structure, and function, addressing the vast sequence space versus limited structure space paradox.