Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Histidine-proline-rich glycoprotein (HPRG) is a serum protein synthesized in the liver and internalized by various cells, including skeletal muscle.
• HPRG possesses a multidomain structure with N-terminal cystatin-homologous modules and a C-terminal region containing histidine-proline-rich (HPRR) and proline-rich regions (PRR1, PRR2).
• While HPRG binds ligands and modulates angiogenesis, the structural basis for its functions, especially concerning the disordered HPRR, remains unclear.

Purpose of the Study:

• To elucidate the structural basis of HPRG's function, particularly its role as an intracellular zinc chaperone.
• To investigate the evolutionary changes in the PRR1 domain and their implications for HPRG's zinc-binding capabilities.
• To provide a structural foundation for HPRG's suggested involvement in maintaining the quaternary structure of skeletal muscle AMP deaminase (AMPD).

Main Methods:

• Comparative analysis of the PRR1 sequence across mammalian species.
• Secondary structure prediction of the HPRR.
• Identification of conserved zinc-binding sites within the PRR1 domain.

Main Results:

• A conserved binding site in PRR1 across mammalian species was identified, capable of coordinating Zn(2+) ions.
• This binding site exhibits an amino acid arrangement compatible with experimentally identified cysteine-containing sites in rabbit HPRG.
• Evolutionary analysis revealed a structural change in the PRR1 Zn(2+) binding site during Anthropoidea evolution, forming a motif similar to those in metal transporters and metallochaperones.

Conclusions:

• The findings provide a structural basis for HPRG's function as an intracellular zinc chaperone.
• The conserved Zn(2+) binding site in PRR1 is crucial for HPRG's role in maintaining the quaternary structure of skeletal muscle AMPD.
• Evolutionary modifications of the PRR1 zinc-binding site highlight its importance in HPRG function and adaptation.