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Protein–protein interactions: switch from classical methods to proteomics and bioinformatics-based approaches

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Abstract

Following the sequencing of the human genome and many other organisms, research on protein-coding genes and their functions (functional genomics) has intensified. Subsequently, with the observation that proteins are indeed the molecular effectors of most cellular processes, the discipline of proteomics was born. Clearly, proteins do not function as single entities but rather as a dynamic network of team players that have to communicate. Though genetic (yeast two-hybrid Y2H) and biochemical methods (co-immunoprecipitation Co-IP, affinity purification AP) were the methods of choice at the beginning of the study of protein–protein interactions (PPI), in more recent years there has been a shift towards proteomics-based methods and bioinformatics-based approaches. In this review, we first describe in depth PPIs and we make a strong case as to why unraveling the interactome is the next challenge in the field of proteomics. Furthermore, classical methods of investigation of PPIs and structure-based bioinformatics approaches are presented. The greatest emphasis is placed on proteomic methods, especially native techniques that were recently developed and that have been shown to be reliable. Finally, we point out the limitations of these methods and the need to set up a standard for the validation of PPI experiments.

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Abbreviations

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

BN-PAGE:

Blue native PAGE

CN-PAGE:

Colorless native PAGE

Mw:

Molecular weight

WB:

Western blotting

MS:

Mass spectrometry

LC–MS/MS:

Liquid chromatography mass spectrometry

MALDI-MS:

Matrix-assisted laser desorption ionization mass spectrometry

m/z :

Mass/charge

CID:

Collision-induced dissociation

ATP:

Adenosine triphosphate

GTP:

Guanosine triphosphate

RNA:

Ribonucleic acid

PTMs:

Post-translational modifications

PPIs:

Protein–protein interactions

Y2H:

Yeast two-hybrid

TAP-MS:

Tandem affinity purification-MS

FRET:

Fluorescence resonance energy transfer

AP-MS:

Affinity purification-MS

DNA:

Deoxyribonucleic acid

NR:

Non-reducing

R:

Reducing

IgG:

Immunoglobulin G

AUC:

Analytical ultracentrifugation

SEC:

Size exclusion chromatography

IEF:

Isoelectric focusing

EM:

Electron microscope

CAD:

Collision-activated dissociation

ECD:

Electron capture dissociation

ETD:

Electron transfer dissociation

DESI:

Desorption-ESI

TNF-α:

Tumor necrosis factor alpha

ICP-MS:

Inductively coupled plasma-MS

IP:

Immunoprecipitation

IMS-MS:

Ion mobility spectrometer-MS

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Acknowledgments

We would like to thank Ms. Laura Mulderig, Scott Nichols, and their colleagues (Waters Corporation) for their generous support in setting up the Proteomics Center at Clarkson University. CCD thanks Drs. Thomas A. Neubert (New York University) and Belinda Willard (Cleveland Clinic), and Drs. Gregory Wolber and David Mclaughin and Ms. Cathy Leyer (Eastman Kodak Company) for donation of a TofSpec2E MALDI-MS (each). This work was supported in part by Clarkson University (start-up grant to CCD), private donations (Ms. Mary Stewart Joyce and Mr. Kenneth Sandler), the Redcay Foundation (SUNY Plattsburgh), SciFund Challenge donors and by the U.S. Army research office through the Defense University Research Instrumentation Program (DURIP grant #W911NF-11-1-0304). The authors declare that they have no competing and/or financial interests.

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  1. Department of Chemistry and Biomolecular Science, Biochemistry and Proteomics Group, Clarkson University, 8 Clarkson Avenue, Potsdam, NY, 13699-5810, USA

    Armand G. Ngounou Wetie, Izabela Sokolowska, Alisa G. Woods, Urmi Roy & Costel C. Darie

  2. Centre for Biological Sciences, University of Southampton, Life Sciences Building 85, Southampton, SO17 1BJ, UK

    Katrin Deinhardt

  3. Institute for Life Sciences, University of Southampton, Life Sciences Building 85, Southampton, SO17 1BJ, UK

    Katrin Deinhardt

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  1. Armand G. Ngounou Wetie
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Correspondence to Costel C. Darie.

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Ngounou Wetie, A.G., Sokolowska, I., Woods, A.G. et al. Protein–protein interactions: switch from classical methods to proteomics and bioinformatics-based approaches. Cell. Mol. Life Sci. 71, 205–228 (2014). https://doi.org/10.1007/s00018-013-1333-1

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