What do dysfunctional serpins tell us about molecular mobility and disease?

@article{Stein1995WhatDD,
  title={What do dysfunctional serpins tell us about molecular mobility and disease?},
  author={Penelope E. Stein and Robin W. Carrell},
  journal={Nature Structural Biology},
  year={1995},
  volume={2},
  pages={96-113}
}
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… 

Topics from this paper

The biostructural pathology of the serpins: critical function of sheet opening mechanism.
TLDR
The combined results emphasise the critical part played by residues involved in the sliding movement that opens the A-sheet to allow reactive loop insertion and conclude that changes in these residues provide the prime explanation for the ready conversion of PAI-1 to the inactive latent state.
The Serpins: Nature's Molecular Mousetraps
TLDR
The solving of the structure of this complex of serpins completes a video depiction of the changes involved and shows how this conformational shift not only inhibits the protease but also destroys it.
Human genetics and disease: Serpinopathies and the conformational dementias
TLDR
The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.
Serpins and the Diversity of Conformational Diseases
The diverse members of the serpin family of protease inhibitors can each typically undergo a profound change in conformation. Aberrations of this conformational transition frequently occur and lead
Serpins Flex Their Muscle
TLDR
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.
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
TLDR
Therapeutic strategies are now being developed to block the aberrant conformational transitions and so treat the serpinopathies.
Dysfunctional variants and the structural biology of the serpins.
TLDR
From the beginning, the study of the serpins has been a collective process with the understanding of the function of each member being greatly strengthened by parallel studies of other serpins, and the lessons learnt from the human dysfunctional variants have opened understanding to a degree that far surpasses the contribution of more conventional approaches.
Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease.
  • B. Gooptu, B. Hazes, +4 authors D. Lomas
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
TLDR
This intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.
Serpins (Serine Protease Inhibitors)
TLDR
Protocols to determine the second‐order rate constant of AT inhibition of thrombin in the absence and presence of heparin and a partial list of other serpins and their purification methods are presented.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 102 REFERENCES
Crystal structure of an uncleaved serpin reveals the conformation of an inhibitory reactive loop
TLDR
A comparison of the current model with that of its cleaved counterpart suggests that the conformational ‘stress’ of the serpin in its uncleaved and uncomplexed state may not be confined solely to the reactive loop or β–sheet A.
COOH-terminal Substitutions in the Serpin C1 Inhibitor That Cause Loop Overinsertion and Subsequent Multimerization (*)
TLDR
Investigation of plasmas of patients with the Val Met or Pro Ser substitutions showed that these dysfunctional proteins circulate at low levels and are recognized by the complex-specific monoclonal antibody, which strongly indicates a conformational change as a result of these carboxyl-terminal substitutions.
Crystal structure of ovalbumin as a model for the reactive centre of serpins
TLDR
The structure of native ovalbumin is determined to 1.95 Å resolution and it is found that the intact peptide loop forming the analogue to the reactive centre of the inhibitory serpins takes the unexpected form of a protruding, isolated helix.
The intact and cleaved human antithrombin III complex as a model for serpin–proteinase interactions
TLDR
The intact reactive site loop is in a novel conformation that seems well suited for interaction with proteinases such as thrombin and blood coagulation factor Xa.
Structural transition of α1‐antitrypsin by a peptide sequentially similar to β‐strand s4A
Crystal structure studies have shown that cleaved and intact serpins differ essentially in the topology of β-sheet A. This is five-stranded in the intact molecules and six-stranded after cleavage by
C1 inhibitor hinge region mutations produce dysfunction by different mechanisms
TLDR
A “hinge” region mutation in C1 inhibitor with a Val to Glu replacement is identified at P14 Val–432, resulting in dysfunction by different mechanisms: in one (P14 Val→Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala→Thr), interaction with target protease is blocked.
Mobile reactive centre of serpins and the control of thrombosis
TLDR
It is shown here that the reactive centre of the serpins can adopt varying conformations and that mobility of the reactive centres is necessary for the function of antithrombin and its binding and activation by heparin and the identification of a new locked conformation explains the latent inactive state of PAI-1.
Molecular basis of inherited human antithrombin deficiency
TLDR
The molecular elucidation, over the past decade, of the various AT deficiency types has provided important new insights into functional-structural relationships of AT, which might lead to the production of AT molecules that are specifically genetically engineered to be of use in a variety of clinical situations.
...
1
2
3
4
5
...