Induced fit, folding, and recognition of the NF-kappaB-nuclear localization signals by IkappaBalpha and IkappaBbeta

• Published in: Journal of molecular biology Vol. 367; no. 1; pp. 262 - 274
• Main Authors: Lätzer, Joachim, Papoian, Garegin A, Prentiss, Michael C, Komives, Elizabeth A, Wolynes, Peter G
• Format: Journal Article
• Language: English
• Published: England 16.03.2007
• Subjects: Computer Simulation; I-kappa B Proteins - physiology; Models, Molecular; NF-kappa B - chemistry; NF-kappa B - metabolism; NF-kappa B p50 Subunit - chemistry; NF-kappa B p50 Subunit - metabolism; NF-KappaB Inhibitor alpha; Nuclear Localization Signals - physiology; Nuclear Proteins - chemistry; Nucleoplasmins; Phosphoproteins - chemistry; Protein Folding; Signal Transduction
• ISSN: 0022-2836

Protein structure prediction codes based on the associative memory Hamiltonian were used to probe the binding modes between the nuclear localization signal (NLS) polypeptide of NF-kappaB and the inhibitors IkappaBalpha and IkappaBbeta. Experimentally, it is known that the NLS polypeptide is unstructured in the NF-kappaB complex with DNA but it forms an extended helical structure with the NLS (residues 301-304) between the two helices in the NF-kappaB/IkappaBalpha complex. The simulations included the NF-kappaB(p65) and (p50) NLS polypeptides and various mutants alone and in the presence of IkappaBalpha and IkappaBbeta. The simulations predict that the NLS polypeptide by itself binds tightly to IkappaBalpha and IkappaBbeta. In the NF-kappaB (p50/p65) heterodimer, the p50 NLS is predicted to remain free to bind to importin alpha. In the interaction with IkappaBalpha, both p65 NLSs are predicted to be bound. In IkappaBbeta, the NLS polypeptide binds to two binding sites, as seen in the crystal structure, with one site heavily favored for stable binding.