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Structure-function relationships of the human Runx1 transcription factor
KTH, Superseded Departments, Biotechnology.
2001 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Runx transcription factors contain a DNA-binding andtransactivating α-subunit and a β-subunit (CBFβ)that serves to increase the DNA binding affinity of theα-subunit. The DNA binding domain of Runx proteins isnamed the Runt homology domain (RD) after its strong sequencehomology to theDrosophilaprotein Runt. Biological functions that aredependent on Runx proteins are for instance bloodcelldevelopment and formation of bone. The human diseases acutemyeloid leukemia and cleidocranial dysplasia have been linkedtoRunx1andRunx2, respectively.

The structure of CBFβ was solved with NMR spectroscopy.There are no substantial structural differences between our apostructure and CBFβ in a crystallographic dimericRD-CBFβ structure.15N NMR relaxation measurements show that almost thecomplete backbone is rigid with high order parameters. Only alimited number of residues display relaxation behaviorindicative of conformational exchange processes on themicrosecond to millisecond timescale. Overall, localflexibility does not appear to influence the RD binding byCBFβ.

The crystallographic structure of the apo RD reveals thatthe fold is immunoglobulin-like with strong structural homologyto several other transcription factors such as STAT-1 and NFAT.We suggest that the sequence specificity and DNA bindingaffinity of immunoglobulin domains, in part, is governed by thelength and composition of two conserved DNA binding loops.Several diseases related missense mutations in the RD can beunderstood at the molecular level with our structure. We alsoshow that the N-terminal sequence of Runx1 together withchloride ions or other negative entities can influence the DNAbinding ability of the RD.

Keywords:Runx1, Runt domain, CBFβ, transcription,leukemia, protein structure, protein dynamics

Place, publisher, year, edition, pages
Stockholm: Bioteknologi , 2001. , viii, 38 p.
Keyword [en]
Runx1, Runt domain, CBFâ, transcription, leukemia, protein structure, protein dynamics
URN: urn:nbn:se:kth:diva-3167ISBN: 91-7283-084-0OAI: diva2:8934
Public defence
NR 20140805Available from: 2001-05-31 Created: 2001-05-31Bibliographically approved

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