An expanding universe of small proteins

Abstract

Historically, small proteins (sproteins) of less than 50 amino acids, in their final processed forms or genetically encoded as such, have been understudied. However, both serendipity and more recent focused efforts have led to the identification of a number of new sproteins in both Gram-negative and Gram-positive bacteria. Increasing evidence demonstrates that sproteins participate in a wide array of cellular processes and exhibit great diversity in their mechanisms of action, yet general principles of sprotein function are emerging. This review highlights examples of sproteins that participate in cell signaling, act as antibiotics and toxins, and serve as structural proteins. We also describe roles for sproteins in detecting and altering membrane features, acting as chaperones, and regulating the functions of larger proteins.

Fig 1

Small secreted proteins exhibit diversity in their three-dimensional structures and can contain unique intramolecular linkages or modified amino acids. For example, the mature form of (a) subtilosin (PDB: 1PXQ) is cyclized in a head-to-tail fashion and contains three unique linkages between cysteine sulfur atoms and α-carbons of phenylalanine and threonine. In contrast, (b) leucocin A (PDB: 1CW6) has a single disulfide bond [43,44].

Fig. 2

Small proteins (shown in red) interact with integral membrane proteins in a number of different ways. (a) PetG and PetN are transmembrane proteins that associate with the periphery of the cytochrome ^b6^f complex (PDB: 2E74) and are required for its stabilization in Synechocystis PCC 6803 [6,45]. PetM is thought to have a regulatory role [29]. (b) Sda forms a complex with the soluble portion of KinB (PDB: 3D36) to block the initiation of endospore formation in Bacillus species [46].