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Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding
Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

The crucial role of c-Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of c-Myc function. The transactivation domain of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of c-Myc-1-88, where hierarchical phosphorylation of T58 and S62 regulates activation and destruction of the c-Myc protein. By NMR chemical shift analysis, relaxation measurements and NOE analysis, we show that both the MBI region (residues 45-65) and residues 22-33 are transiently structured regions, conserved also in other members of the Myc family. Binding of Bin1-SH3 to c-Myc-1-88 as assayed by NMR and SPR revealed primary binding to the S62 region, but also a dynamically disordered and multivalent complex in which intrinsic disorder of c-Myc-1-88 was retained while releasing transient intramolecular interactions. Our findings describe a novel mode of regulatory recognition of c-Myc that is in agreement with the increasingly recognized capability of intrinsically disordered regions to efficiently mediate transient interactions with a wide range of targets, with important implications towards understanding the unique multifaceted biological functions of c-Myc.

Nationell ämneskategori
Naturvetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-70832OAI: oai:DiVA.org:liu-70832DiVA, id: diva2:441971
Tillgänglig från: 2011-09-20 Skapad: 2011-09-20 Senast uppdaterad: 2011-09-20Bibliografiskt granskad
Ingår i avhandling
1. Protein Structure and Interaction in Health and Disease
Öppna denna publikation i ny flik eller fönster >>Protein Structure and Interaction in Health and Disease
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis focuses on protein structure, dynamics and interaction and their relation to human disease. In particular, the biophysical and structural properties of both well-ordered and partially disordered proteins are studied using a range of biophysical techniques such as circular dichroism spectroscopy, fluorescence spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. Pseudomonas aeruginosa is a human pathogen due to its multidrug resistance (MDR) caused by overexpression of efflux pump systems. This thesis describes how MDR mutations within the MexR repressor of the MexAB-OprM system reduce the DNA affinity by altering its stability with maintained structure. The oncogenic protein c-Myc is involved in many essential biological functions such as cell proliferation, differentiation and apoptosis and is also highly associated with several forms of human cancers, and where the N-terminal domain is regulated by a plethora of protein interactions. In this thesis the intrinsically disordered N-terminal part of c-Myc and its interactions with the proteins Bin1 and TBP are described. Myc binds Bin1 with maintained disorder in a multivalent manner, which may explain why the onco-protein can interact with such a wide range of binding partners. A similarly dynamic interaction is observed for Myc with the TATA-binding protein (TBP). The essential human multidomain glutaredoxin Grx3 is associated with several biological functions such as redox signaling, proliferation and signal transduction. We have solved the structure and analyzed the dynamic properties in the ps-ns and ms time scale for the two N-terminal domains, providing a platform for further analysis of the Grx3 protein and its interactions. Taken together, this thesis emphasizes the importance of joint structural, biophysical and dynamic studies to better understand protein function in health and disease.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2011. s. 67
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1394
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:liu:diva-70837 (URN)978-91-7393-077-2 (ISBN)
Disputation
2011-10-07, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 14:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2011-09-20 Skapad: 2011-09-20 Senast uppdaterad: 2019-12-19Bibliografiskt granskad

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Andrésen, CeciliaHelander, SaraCarlsson, JonasLundström, PatrikSunnerhagen, Maria

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Andrésen, CeciliaHelander, SaraCarlsson, JonasLundström, PatrikSunnerhagen, Maria
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