Intrinsically disordered protein (JMolGraphMod)

An extensive overview paper citing 289 references.

[edit] 1 Intro

• 1894 Fischer -- lock and key hypothesis for enzyme and glucoside
• Experiments supported view that function depends on 3D structure
• Highly specific 3D structure became accepted as a necessary prerequisite for protein function (pg 27)

• molten globule (pg 28) -- refers to liquidlike, partially folded state; an intermediate between ordered state and random coil

[edit] 2 Protein Trinity

Old paradigm: Amino-acid sequence -> 3 Dimensional Structure -> Function

New paradigm: Function can arise from any of three protein forms (ordered, molten globule, and random coil) and the transitions between them (pg 30), such as disorder-to-order transitions on binding (pg 35). (definition of cooperativity)

[edit] 3 Determining Disorder (pg 29-30)

• X-ray crystallography -- disorder leads to missing electron density, some uncertainty
• NMR spectroscopy -- underrepresents molten globules
• Circular dichroism (CD) spectroscopy -- estimates of secondary structure and distinguishing ordered and molten globular from from random coil
• Protease digestion -- disordered regions have higher sensitivity to protease digestion
• Stoke's radius determination -- abnormally large radii for a given molecular weight evidence for disorder

[edit] 4 Disorder and Molecular Recognition

• a protein undergoing a disorder-to-order transition upon binding subtracts free energy to organize the disordered region and could lead to high specificity with low affinity (pg 38)

• disorder-to-order binding can overcome steric restrictions (?) and enable larger interaction surfaces than rigid partners (pg 38)

• order to disorder conversion could lead to increase or discreases in rates of association and increases in rates of dissociation (pg 39)

• flexibility can raise or lower binding affinities and raise or lower on-rates and off-rates compared to rigid partners. the binding affinities of rigid partners can increase or decrease through mutation (pg 39)

[edit] 5 Comparison between ordered and disordered protein segments

Amino acids (pg 44):

• order-promoting: W, C, F, I, Y, V, L, N
• disorder promoting: A, R, G, Q, S, P, E, K
• neutral: H, M, T, D

Attributes (pg 45-46):

• Hydropathy: increased likelihood in order
• Flexibility: increased likelihood in disorder
• Net charge: disorder likelihood increases at the extremes, ordered between -.1 and .1
• Aromaticity: increased likelihood in order
• Coordination number: increased likelihood in order
• Sequence complexity: a class of disordered protein structures has very low sequence complexity