Exploring Structure-Function Relationships in Moonlighting Proteins

Sayoni Das1, Ishita Khan2, Daisuke Kihara3, and Christine Orengo1

  • 1 Institute of Structural and Molecular Biology, University College London, Gower Street, London, UK
  • 2 Department of Computer Science, Purdue University, North University Street, West Lafayette, Indiana, USA
  • 3 Department of Biological Sciences, Purdue University, Martin Jischke Drive, West Lafayette, Indiana, USA


As the availability of large-scale genomic data and the technical advancements in high-throughput biological experiments reach an astonishingly high level, the functional characterization of proteins becomes more sophisticated than ever. Consequently, an increasing number of proteins have been found to moonlight, that is, perform multiple independent cellular functions within a single polypeptide chain (see Chapter 1 for more details of the definition of protein moonlighting).

The functional diversity of moonlighting proteins is not a consequence of gene fusions, splice variance, proteins performing different functions in different cellular contexts, varying post-transcriptional modifications, homologous but non-identical proteins, or multiple photolytic fragments. The multiple roles of moonlighting proteins are not restricted to certain organisms or protein families, nor do they have a common mechanism through which they switch between different functions. Experimentally identified moonlighting proteins have been shown to switch functions as a consequence of changes in cellular locations within and outside the cell, expression in different cell types, oligomerization states, ligand binding locations, binding partners, and complex formation [1-3].

A large number of moonlighting proteins have been found to be involved in bacterial virulence, DNA synthesis or repair, cancer cell motility, and angiogenesis, among others. As an example, neuropilin is a moonlighting protein that is known to show diverse functions due to changes in cellular contexts. In endothelial cells, it is a vascular endothelial cell growth factor (VEGF) receptor and a major regulator of angiogenesis, vasculogenesis, and vascular permeability. However, in nerve axons, it is a receptor for a different ligand (Semaphorin III) and mediates neuronal cell guidance.

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections, First Edition. Edited by Brian Henderson.

© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

More than 300 moonlighting proteins are known in the literature today (see Chapter 1); however, the rapid increase in the number of identified moonlighting proteins suggests that the phenomenon may be common in all kingdoms of life. So far, the moonlighting function(s) of the known proteins have mostly been discovered by serendipity and little is known about the molecular mechanisms of such moonlighting actions [2]. Consequently, any efforts to characterize the molecular mechanisms of such proteins and understand their structure-function relationship would aid in identifying new moonlighting functions and help to better understand of the complex functional interplay of moonlighting proteins in the cell.

In this chapter, we first briefly discuss the different contexts in which protein function can be described, the complex structure-function relationship in proteins, followed by the current approaches used in identifying and characterizing moonlighting proteins. We then propose a classification of moonlighting proteins based on the structure-function analysis of selected moonlighting proteins. A few examples of moonlighting proteins in each classification are described in detail, many of which are implicated in bacterial virulence. Finally, we describe some general trends observed in the analysis which will, we hope, be valuable in understanding how a moonlighting protein can perform more than one unrelated function.

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