Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding

Andrésen, CeciliaLinköpings universitet,Molekylär Bioteknik,Tekniska högskolan (författare)

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.

Helander, SaraLinköpings universitet,Molekylär Bioteknik,Tekniska högskolan(Swepub:liu)sarhe49 (författare)
Lemak, AlexanderDepartment of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada (författare)
Farès, ChristopheDepartment of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada (författare)
Csizmok, VeronikaMolecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada (författare)
Carlsson, JonasLinköpings universitet,Molekylär Bioteknik,Tekniska högskolan(Swepub:liu)jonca19 (författare)
Penn, Linda Z.Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada (författare)
Forman-Kay, Julie D.Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada (författare)
Arrowsmith, Cheryl H.Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada (författare)
Lundström, PatrikLinköpings universitet,Molekylär Bioteknik,Tekniska högskolan(Swepub:liu)patlu71 (författare)
Sunnerhagen, MariaLinköpings universitet,Molekylär Bioteknik,Tekniska högskolan(Swepub:liu)marsu05 (författare)
Linköpings universitetMolekylär Bioteknik (creator_code:org_t)

Av författaren/redakt...: Andrésen, Cecili ...; Helander, Sara; Lemak, Alexander; Farès, Christoph ...; Csizmok, Veronik ...; Carlsson, Jonas; visa fler...; Penn, Linda Z.; Forman-Kay, Juli ...; Arrowsmith, Cher ...; Lundström, Patri ...; Sunnerhagen, Mar ...; visa färre...

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