Effects of proline cis-trans isomerization on TB domain secondary structure.
The transforming growth factor beta (TGF-beta) binding protein-like (TB) domain is found principally in proteins localized to extracellular matrix fibrils, including human fibrillin-1, the defective protein in the Marfan syndrome. Analysis of the nuclear magnetic resonance (NMR) data for the sixth TB module from human fibrillin-1 has revealed the existence of two stable conformers that differ in the isomerization states of two proline residues. Unusually, the two isoforms do not readily interconvert and are stable on the time scale of milliseconds. We have computed independent structures of the major and minor conformers of TB6 to assess how the domain fold adjusts to incorporate alternatively cis- or trans-prolines. Based on previous observations, it has been suggested that multiple conformers can only be accommodated in flexible regions of protein structure. In contrast, P22, which exists in trans in the major form and cis in the minor form of TB6, is in a rigid region of the domain, which is confirmed by backbone dynamics measurements. Overall, the structures of the major and minor conformers are similar. However, the secondary structure topologies of the two forms differ as a direct consequence of the changes in proline conformation.
Yuan
X
X
Department of Biochemistry, University of Oxford, United Kingdom.
Werner
J M
JM
Knott
V
V
Handford
P A
PA
Campbell
I D
ID
Downing
K
K
D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008382:Marfan Syndrome / Q000235:genetics; D008840:Microfilament Proteins / Q000737:chemistry*; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016212:Transforming Growth Factor beta / Q000737:chemistry*; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D011392:Proline; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines