Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions.
Inhibitory serpins are metastable proteins that undergo a substantial conformational rearrangement to covalently trap target peptidases. The serpin reactive center loop contributes a majority of the interactions that serpins make during the initial binding to target peptidases. However, structural studies on serpin-peptidase complexes reveal a broader set of contacts on the scaffold of inhibitory serpins that have substantial influence on guiding peptidase recognition. Structural and biophysical studies also reveal how aberrant serpin folding can lead to the formation of domain-swapped serpin multimers rather than the monomeric metastable state. Serpin domain swapping may therefore underlie the polymerization events characteristic of the serpinopathies. Finally, recent structural studies reveal how the serpin fold has been adapted for non-inhibitory functions such as hormone binding.
Whisstock
James C
JC
From the Department of Biochemistry and Molecular Biology and ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia. james.whisstock@monash.edu.au
Silverman
Gary A
GA
Bird
Phillip I
PI
Bottomley
Stephen P
SP
Kaiserman
Dion
D
Luke
Cliff J
CJ
Pak
Stephen C
SC
Reichhart
Jean-Marc
JM
Huntington
James A
JA
D000818:Animals; D001692:Biological Transport; D001703:Biophysics / Q000379:methods; D020134:Catalytic Domain; D006728:Hormones / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015843:Serpins / Q000737:chemistry / Q000502:physiology*; D013379:Substrate Specificity; D013917:Thrombin / Q000737:chemistry
D006728:Hormones; D015843:Serpins; D010447:Peptide Hydrolases; D013917:Thrombin