SLiMs

Short linear motifs (SLiMs) are short, linear stretches of amino acids within proteins, typically 3–10 residues long, that mediate key cellular interactions. They are usually embedded in larger proteins and commonly reside in intrinsically disordered regions, where they can be accessible and flexible. Because of their brevity and sequence degeneracy, SLiMs can arise and disappear rapidly over evolutionary time, and their activity is highly context-dependent, relying on surrounding sequence, structure, and cellular conditions.

Function and recognition: SLiMs act as molecular handles that recruit binding partners, enzymes, or regulatory machinery. They often interface with modular domains such as SH3, PDZ, WW, or 14-3-3, or serve as sites for post-translational modification, localization signals, or proteolysis. Consequently SLiMs participate in signaling networks, endocytosis, trafficking, DNA repair, and transcriptional regulation. They can be exploited by pathogens to hijack host processes, illustrating the functional importance of these motifs. Evolutionarily, SLiMs contribute to rapid remodeling of interaction networks due to their small size and permissive sequence requirements.

Prediction and validation: Identifying SLiMs is challenging because of degeneracy and context dependence. Computational approaches include pattern-based searches, position-specific scoring matrices, and machine-learning methods trained on known motifs. Experimental validation often employs peptide libraries, phage display, proteomics, or mutational analyses to test binding, modification, or functional effects in cells.

Examples: Well-known SLiMs include SH3-binding PxxP motifs, C-terminal PDZ-binding motifs, degrons such as DSGxxS recognized by certain ubiquitin ligases, and 14-3-3 binding motifs like RSXpSXP. Kinase phosphorylation motifs also function as SLiMs within signaling networks.