Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online





Learning Goals/Objectives for Chapter 5C:  After class and this reading, students will be able to

  • explain the similarities and differences in structure between myoglobin and hemoglobin in the deoxy and oxy states
  • state structural features of Hb that stabilizes the deoxystate and the oxystate
  • draw graphs of fractional saturation Y vs L (or pO2) for Mb and Hb  (at different pHs and in the presence of CO2 for Hb) and explain their apparent similarities and differences
  • draw a thermodynamic cycle for the interactions of O2, CO2 and H+ with deoxy-Hb and oxy-Hb
  • explain how Hill Plot analysis can account for cooperative binding curves for Hb.
  • give a simple explanation of the MWC model and draw cartoon representations of Hb in the T and R state, describing the characteristics of those states
  • given definitions of the MWC parameters (L, KT, KR, c, and α) and the assumptions of the model, explain how this model accounts for cooperative sigmoidal binding curves for Hb and dioxygen.
  • draw cartoon models and explain differences in lock and key, induced fit, and conformational selection as mechanisms for ligand bind.
  • Explain biological advantages elicited on ligand binding by intrinsically disordered proteins

C7.  Binding to Intrinsically Disorder Protein and MORFs

As described above, binding of a protein to a ligand (including another protein) could occur by a lock and key mechanism, possibly through a conformational selection process, or through an induced fit when an initial binding event is followed by a conformation rearrangement to form a more tightly bound complex.  But how does binding to completely intrinsically disorder protein (which has been documented) occur?  These cases are quite removed from those envisioned in simple induced fit mechanisms.  To accommodate binding to IDPs, a new idea has emerged, that of Molecular Recognition Features (MoRFs). 

MoRFs are typically contiguous but disordered sections of a protein that first encounter a binding partner (a protein for example).  Using protein complexes in the Protein Data Bank, Mohan et al conducted a structural study of MoRFs by selecting short regions (less than 70 amino acids) from mostly disordered proteins that were bound to proteins of greater than 100 amino acids.  They chose a sequence size of 70 amino acids and smaller since they would be most likely to display conformational flexibility before binding to a target.  2512 proteins fit their criteria.  For comparison, they created a similar database of ordered monomeric proteins.  The analysis showed that after they encounter a binding surface on another protein, the MoRF would adopt or "morp" into several types of new conformations, including alpha-helices (a-MoRFs), beta-strands (b-MoRFs),  irregular strands (i-MoRFs) and combined secondary structure (complex-MoRFs), as shown in the figure below.

Figure: Types of Molecular Recognition Features in Intrinsically Disordered Proteins

(A) α-MoRF, Proteinase Inhibitor IA3, bound to Proteinase A (PDB entry 1DP5). (B) A β-MoRF, viral protein pVIc, bound to Human Adenovirus 2 Proteinase (PDB entry 1AVP). (C) An ι-MoRF, Amphiphysin, bound to α-adaptin C (PDB entry 1KY7). (D) A complex-MoRF, β-amyloid precursor protein (βAPP), bound to the PTB domain of the neuron specific protein X11 (PDB entry 1X11). Partner interfaces (gray surface) are also indicated.  Vacic, V. et al. Journal of Proteome Research 6, 2351 (2007). Permission from Copyright Clearance Center's Rightslink /American Chemical Society

Vacic et al have further characterized the binding surfaces between MoRFs and their binding partners using structural data from PDB files.  Interfaces were studied by determining the differences in accessible surface area between MoRFs and their binding partners, and the protein in unbound states.  These were compared to ordered protein complexes, including homodimers and antibody-protein antigen interactions that were not characterized by disordered interactions.   Their findings are summarized below.



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 Archived version of full Chapter 5C:  Model Binding Systems


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