Advanced Topics

Short Linear Motifs (SLiMs)

Summary

SLiMs are compact, degenerate amino acid sequences (3-10 residues) that mediate transient protein-protein interactions. Found in disordered regions, they undergo coupled folding and binding.

Key Points

  • 13-10 residue functional units in disordered regions
  • 2Low affinity but high specificity interactions
  • 3Can evolve de novo by point mutations
  • 4Frequently mimicked by viruses to hijack host networks

Short Linear Motifs represent a distinct mode of protein function, packing remarkable functional density into minimal sequence elements.

Definition and Properties

SLiMs are:

- Short: Typically 3-10 amino acids

- Degenerate: Only a few positions are highly constrained

- Located in disordered regions: Accessible and flexible

- Functional: Mediate interactions, modifications, localization

Types of SLiMs

Ligand Binding Motifs

Recognized by modular binding domains:

- PxxP: SH3 domain binding

- pTyr-X-X-Φ: SH2 domain binding

- NPxY: PTB domain binding

- KDEL: ER retention signal

Modification Sites

Consensus sequences for PTM enzymes:

- S/T-P: Proline-directed kinases (CDK, MAPK)

- R-X-X-S/T: AGC kinases (PKA, PKB)

- K-X-X-K: Ubiquitin ligase motifs

Targeting Signals

Direct subcellular localization:

- NLS (Nuclear Localization Signal): K-K/R-X-K/R

- NES (Nuclear Export Signal): Φ-X₂₋₃-Φ-X₂₋₃-Φ-X-Φ

- ER signal peptide: N-terminal hydrophobic

Binding Properties

SLiM-domain interactions have characteristic kinetics:

- Low affinity: Typically 1-150 μM Kd

- High specificity: Few positions determine binding

- Rapid kinetics: Fast on/off rates

- Reversibility: Ideal for transient signaling

Coupled Folding and Binding

SLiMs typically don't have structure in isolation:

  • Exist as flexible, disordered sequences

    • 2. Upon encountering binding partner, fold into defined structure

  • Often adopt extended or β-strand conformations in bound state

    • Evolutionary Implications

    The short length of SLiMs has profound evolutionary consequences:

    Rapid Evolution

    - Can arise de novo by point mutations

  • 3-10 amino acids = 9-30 nucleotides
  • New interaction surfaces readily evolve

    • Convergent Evolution

  • Same motif evolves independently multiple times
  • Functional constraints, not common ancestry

    • Viral Mimicry

    Viruses frequently evolve SLiMs to hijack host systems:

    - Adenovirus E1A: Mimics cellular LXCXE motif to bind Rb

    - HPV E7: Same strategy for cell cycle disruption

  • Enables manipulation of host signaling networks

    • SLiM Resources

    Computational databases catalog known SLiMs:

    - ELM (Eukaryotic Linear Motif resource)

  • Enable prediction and functional annotation
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    Intrinsically Disordered Proteins (IDPs)
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