What do dysfunctional serpins tell us about molecular mobility and disease?
Proteinase inhibitors of the serpin family have a unique ability to regulate their activity by changing the conformation of their reactive-centre loop. Although this may explain their evolutionary success, the dependence of function on structural mobility makes the serpins vulnerable to the effects of mutations. Here, we describe how studies of dysfunctional variants, together with crystal structures of serpins in different forms, provide insights into the molecular functions and remarkable folding properties of this family. In particular, comparisons of variants affecting different serpins allow us to define the domains which control this folding and show how spontaneous but inappropriate changes in conformation cause diverse diseases.
Stein
P E
PE
Department of Haematology, University of Cambridge, MRC Centre, UK.
Carrell
R W
RW
D000799:Angioedema / Q000235:genetics; D000991:Antithrombins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D001665:Binding Sites; D003174:Complement C1 Inactivator Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D004194:Disease / Q000209:etiology*; D004646:Emphysema / Q000235:genetics; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D005810:Multigene Family; D011485:Protein Binding; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency
D000991:Antithrombins; D003174:Complement C1 Inactivator Proteins; D015843:Serpins; D000515:alpha 1-Antitrypsin; D006493:Heparin; D012697:Serine Endopeptidases