Multiple Forms of Multifunctional Proteins in Health and Disease

Abstract

Protein science has moved from a focus on individual molecules to an integrated perspective in which proteins emerge as dynamic players with multiple functions, rather than monofunctional specialists. Annotation of the full functional repertoire of proteins has impacted the fields of biochemistry and genetics, and will continue to influence basic and applied science questions - from the genotype-to-phenotype problem, to our understanding of human pathologies and drug design. In this review, we address the phenomena of pleiotropy, multidomain proteins, promiscuity, and protein moonlighting, providing examples of multitasking biomolecules that underlie specific mechanisms of human disease. In doing so, we place in context different types of multifunctional proteins, highlighting useful attributes for their systematic definition and classification in future research directions.

Keywords: gene ontology; mechanisms of disease; moonlighting proteins; multidomain proteins; pleiotropy; protein promiscuity.

FIGURE 1

Different forms of protein multifunctionality in Ure2p. The Ure2 protein from budding yeast is a peroxidase enzyme that can form prions and is directly involved in nitrogen-catabolite repression by binding to and sequestering phosphorylated transcription factors in the cytoplasm, such as Gln3. (A) Deletion of URE2 results in numerous phenotypes and observable traits related to different cellular pathways, which makes Ure2 a pleiotropic protein; only representative phenotypes associated to ure2Δ are shown. (B) Ure2 is a multidomain protein composed of an unstructured prion domain in addition to two globular domains typical of glutathione S-transferases (GST-N and GST-C). (C) The enzymatic activity of Ure2 is highly promiscuous: in vitro, Ure2 catalyze reactions with diverse substrates, involving different reaction mechanisms, within a single active site. Three different substrates for the glutathione-peroxidase activity of Ure2 are shown (from left to right: cumene hydroperoxide, hydrogen peroxide, and tert-butyl hydroperoxide). (D) The catalytic and binding activities of Ure2 are independent from one another: mutants lacking the Gln3-regulatory activity maintain their catalytic activity and such protein moonlighting is not explained by gene fusion, alternative splicing, or differential proteolysis. Protein images were generated using structure data from Protein Data Bank entry 1GgY, or Raptor X-predicted structures from Uniprot accessions P18494 and P23202.

FIGURE 2

Different kinds of multifunctional proteins. Different kinds of multifunctional proteins may be described based on their “molecular” or “biological” functions. Examples are provided for three multifunctional proteins from S. cerevisiae (Aro1, Sod1, and Aco1); functional annotations (GO terms) are from the Saccharomyces Genome Database (www.yeastgenome.org).