Filling in missing puzzle pieces in protein structural biology with cross-linking mass spectrometry

TL;DR

This paper discusses how cross-linking mass spectrometry can help fill gaps in understanding protein structures, especially in flexible regions and dynamic complexes.

Contribution

The paper highlights novel applications of cross-linking mass spectrometry in capturing protein conformational changes and flexible regions.

Findings

Cross-linking mass spectrometry identifies interactions in flexible protein regions missed by other techniques.

It captures conformational changes in protein complexes across different functional states.

It provides distance constraints for integrative structural modeling and in-cell structural information.

Abstract

High resolution structures of protein complexes provide a wealth of information on protein structure and function. Databases of these protein structures are also used for artificial-intelligence (AI)-based methods of structural modelling. Despite the wealth of protein structures that have been determined by structural biologists, there are still gaps, or missing pieces in the puzzle of protein structural biology. Highly flexible regions may be missing from protein structures and conformational changes of different protein complex states may not be captured by current databases. In this perspective, I sketch out several ways that cross-linking mass spectrometry can contribute to filling in some of these missing pieces: Identification of cross-linked interactions in highly flexible protein regions not captured by other structural techniques; capturing conformational changes of protein complexes in different functional states; serving as distance constraints in integrative structural modelling and providing structural information of in cellulo proteins. The myriad ways in which cross-linking mass spectrometry contributes to filling in missing pieces in structural biology makes it a powerful technique in structural biology.

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