Deciphering post-translational modification codes

Abstract

Post-translational modifications (PTMs) occur on nearly all proteins. Many domains within proteins are modified on multiple amino acid sidechains by diverse enzymes to create a myriad of possible protein species. How these combinations of PTMs lead to distinct biological outcomes is only beginning to be understood. This manuscript highlights several examples of combinatorial PTMs in proteins, and describes recent technological developments, which are driving our ability to understand how PTM patterns may "code" for biological outcomes.

Figure 1

Combinatorial PTMs can code for complex biological outcomes. A. Modifications such as methylation (red), phosphorylation (yellow), or acetylation (blue) are commonly recognized by proteins with PTM-recognition domains (purple and cyan). Modifications such as lysine methylation can occur up to three times on a single residue resulting in PTMs with distinct activity. B. Neighboring PTMs have differing effects on the ability of proteins to recognize a phosphorlyation site. For example, the purple protein requires dimethylation of the lysine, but is occluded by trimethylysine and uninfluenced by the neighboring acetylation. In contrast, the cyan protein can be blocked by aceylation but is uneffected by methylation. C. The combinatorial PTMs setup a “code,” that determines which protein-protein interactions ultimately leading to distinct biological outcomes.

Figure 2

Relationships between experimental approaches and how they are used to decipher the functions of PTM codes. Arrows are meant to designate the use of an approach toward either identifying PTMs, defining coexisting PTMs, and deciphering function. The thickness of each arrow represents the relative extent of contributions.

Figure 3

PTM codes can be exist at varying levels of biological complexity. Two distinct outcomes (State 1 and 2) can be defined for simple linear PTM codes (top), a protein complex (middle), or a functional network consisting of several proteins acting coordinately (bottom). In all cases, differing patterns of PTMs on one or more proteins give rise to discrete biological outcomes.