Positional proteomics: is the technology ready to study clinical cohorts?

Area of Science:

• Biochemistry and Molecular Biology
• Proteomics
• Biomarker Discovery

Background:

• Protein termini and their modifications offer insights into cellular functions.
• Misregulated proteolysis is linked to various human diseases.
• Protein termini are largely unexplored sources for disease-specific analytes.

Purpose of the Study:

• To review methods for defining protein termini.
• To highlight positional proteomics for identifying disease-altered proteoforms and proteolytic processes.
• To discuss challenges and potential of positional proteomics in biomarker research.

Main Methods:

• Review of principal approaches to define protein termini.
• Discussion of recent advances in positional proteomics method development.
• Focus on identifying and tracing specific proteoforms generated by proteolysis.

Main Results:

• Positional proteomics enables unambiguous identification of site-specific, limited proteolysis.
• Proteolytic cleavage generates new proteoforms with altered localization and activity.
• Recent advances have significantly improved sensitivity and throughput in positional proteomics.

Conclusions:

• Positional proteomics offers deep insights into the functional proteome.
• Analysis of proteolytic processes in clinical cohorts is becoming feasible.
• Altered proteolytic processes in disease present opportunities for diagnostic, prognostic, and companion biomarkers.