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The C-terminal sterile alpha motif (SAM) domain of human p73 is a highly dynamic protein, which acquires high thermal
José L Neira1, Paz Sevilla, Francisco García-Blanco
1Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche (Alicante), Spain. jlneira@umh.es
Physical Chemistry Chemical Physics : PCCP
|June 26, 2012
Summary
The sterile alpha motif of p73α (SAMp73) exhibits high thermal stability despite low conformational stability. Its flexibility, particularly in the μs-ms range, is linked to biological functions and explains its thermostability.
Area of Science:
- Biochemistry
- Structural Biology
- Protein Dynamics
Background:
- p73α is a homologue of the tumor suppressor p53.
- SAMp73, a domain within p73α, is crucial for protein-biomolecule interactions.
- SAMp73 displays low conformational stability but high thermal stability.
Purpose of the Study:
- To elucidate the molecular mechanisms behind SAMp73's high thermal stability.
- To investigate the dynamics of SAMp73 across various guanidine hydrochloride concentrations and temperatures.
- To correlate protein flexibility with biological function.
Main Methods:
- Nuclear Magnetic Resonance (NMR) relaxation.
- NMR hydrogen-deuterium exchange (HX).
- Fluorescence lifetime measurements.
Main Results:
- SAMp73 exhibits significant flexibility, with most amide protons undergoing slow μs-ms conformational exchange.
- Residues with higher exchange rates (R(ex)) are involved in molecular binding, linking μs-ms flexibility to biological roles.
- Increased guanidine hydrochloride concentration enhanced pico-to-nanosecond backbone amide proton flexibility in a residue-specific manner.
- Local conformational entropies (m(S(i))) were quantified for the first time.
- Temperature-dependent dynamics revealed decreased flexibility in some residues at higher temperatures, explaining thermostability.
Conclusions:
- SAMp73's high thermal stability is attributed to temperature-dependent dynamics where flexibility decreases with increasing temperature.
- The observed μs-ms flexibility is integral to SAMp73's biological functions, including molecular interactions.
- This study provides novel insights into the relationship between protein dynamics, flexibility, and thermal stability.
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