Summary
IDPs challenge the traditional structure-function paradigm by existing as dynamic conformational ensembles. Their disorder is encoded by low hydrophobicity and high net charge. They drive Liquid-Liquid Phase Separation and enable coupled folding-and-binding.
Key Points
- 1Low hydrophobicity + high charge encodes disorder
- 2Coupled folding-and-binding enables high specificity with reversibility
- 3Primary drivers of liquid-liquid phase separation
- 4Vulnerable to pathological aggregation
Intrinsically disordered proteins represent a paradigm shift in our understanding of protein structure and function.
Challenging the Structure-Function Paradigm
The classical view: "sequence → structure → function"
IDPs demonstrate that stable tertiary structure is not required for function. Instead, many proteins:
- Exist as dynamic conformational ensembles
Sequence Determinants of Disorder
IDP sequences are biased toward:
Low hydrophobicity
High net charge
Low sequence complexity
These features can be used to predict disorder from sequence.
Functional Advantages
Coupled Folding and Binding
IDPs often fold upon binding to partners:
- Reversibility: ideal for signaling
Fly-Casting Mechanism
The extended nature of IDPs increases capture radius:
Structural Plasticity (Promiscuity)
A single IDP can adopt different structures with different partners:
Short Linear Motifs (SLiMs)
IDRs are enriched in SLiMs:
Liquid-Liquid Phase Separation (LLPS)
IDPs are the primary drivers of biomolecular condensates:
IDPs and Disease
The flexibility that enables function also creates vulnerability:
- Aggregation: α-synuclein (Parkinson's), tau (Alzheimer's)
- Aberrant interactions: Disordered regions frequently mutated in cancer
- Phase separation dysregulation: ALS, neurodegeneration