RSS 2.0 Feed

» Welcome Guest Log In :: Register

  Topic: immune system evolution, collecting references to recent articles< Next Oldest | Next Newest >  
rafe gutman

Posts: 27
Joined: May 2002

(Permalink) Posted: July 29 2003,19:04   

more stuff:

Sci Prog 2001;84(Pt 2):125-36

The serpins: nature's molecular mousetraps.

                 Huntington JA, Carrell RW.

University of Cambridge, Department of Haematology, Wellcome Trust Centre for Molecular Mechanisms in
Disease, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK.

A special family of inhibitors, known as the serpins, has evolved an extraordinary mechanism to enable the
control of the proteolytic pathways essential to life. The serpins undergo a profound change in conformation to
entrap their target protease in an irreversible complex. The solving of the structure of this complex now
completes a video depiction of the changes involved. The serpin, just like a mousetrap, is seen to change with
a spring-like movement from an initial metastable state to a final hyperstable form. The structure shows how
this conformational shift not only inhibits the protease but also destroys it. A bonus from these structural
insights is the realisation that a number of diseases, as diverse as thrombosis, cirrhosis and dementia, all share
a common mechanism arising from similar mutations of different serpins.

                 PMID: 11525014 [PubMed - indexed for MEDLINE]

IUBMB Life 2002 Jul;54(1):1-7
                 Serpins: finely balanced conformational traps.

                 Pike RN, Bottomley SP, Irving JA, Bird PI, Whisstock JC.

Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.

Serine protease inhibitors (serpins) play very important roles in the maintenance of various physiologically
important systems. As knowledge of the workings of proteins of this family grows, new understanding is
gained of the mechanisms by which they inhibit target proteases, using conformational changes for which the
structure of serpins is uniquely adapted. This finely balanced system is utilized to healthy benefit in the control
of serpin function by modulators, arguably the most striking examples of which occur in the control of
proteolytic cascades, such as the coagulation system. Serpins also play very important intracellular roles: one
example is the protection of immune cells from their own cytotoxic proteases. The finely balanced serpin
mechanism also means that it is prone to disastrous consequences if mutations should occur in vital positions
in the serpin structure. Many examples of disease-associated mutations have been shown, which has the dual
effect of highlighting how important these molecules are in the maintenance of health and the fine balance that
must be maintained in order to preserve their active, inhibitory conformation.

                 PMID: 12387568 [PubMed - in process]
Curr Opin Struct Biol 2001 Dec;11(6):740-5
                 Serpins and other covalent protease inhibitors.

                 Ye S, Goldsmith EJ.

Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry
                 Hines Boulevard, Dallas, Texas 75390, USA.

Serpins are irreversible covalent 'suicide' protease inhibitors. In the past two years, important advances in the
structural biology of serpins have been forthcoming with the crystal structures of a covalent complex between
trypsin and alpha1-antitrypsin, and of a Michaelis encounter complex between trypsin S195A and serpin 1B
from Manduca sexta. These structures have helped elucidate many aspects of the mechanism of action of
serpins. Also, the crystal structure of the cysteine protease caspase-8 in complex with the inhibitor p35 has
revealed a new family of suicide protease inhibitors.

                 Publication Types:
                     Review, Tutorial

                 PMID: 11751056 [PubMed - indexed for MEDLINE]

Bioessays 1993 Jul;15(7):461-7

                 The role of conformational change in serpin structure and function.

                 Gettins P, Patston PA, Schapira M.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.

 Serpins are members of a family of structurally related protein inhibitors of serine proteinases, with molecular
masses between 40 and 100kDa. In contrast to other, simpler, proteinase inhibitors, they may interact with
proteinases as inhibitors, as substrates, or as both. They undergo conformational interconversions upon
complex formation with proteinase, upon binding of some members to heparin, upon proteolytic cleavage at
the reactive center, and under mild denaturing conditions. These conformational changes appear to be critical
in determining the properties of the serpin. The structures and stabilities of these various forms may differ
significantly. Although the detailed structural changes required for inhibition of proteinase have yet to be
worked out, it is clear that the serpin does undergo a major conformational change. This is in contrast to other,
simpler, families of protein inhibitors of serine proteinases, which bind in a substrate-like or product-like
manner. Proteolytic cleavage of the serpin can result in a much more stable protein with new biological
properties such as chemo-attractant behaviour. These structural transformations in serpins provide
opportunities for regulation of the activity and properties of the inhibitor and are likely be important in vivo,
where serpins are involved in blood coagulation, fibrinolysis, complement activation and inflammation.

                 Publication Types:
                     Review, Tutorial

                 PMID: 8379949 [PubMed - indexed for MEDLINE]

J Biol Chem. 2003 Jul 7 [Epub ahead of print].
                                                                         Related Articles, Links                  
Conserved Ser residues, the shutter region, and speciation in serpin evolution.

Krem MM, Di Cera E.

Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110.

The suicide inhibitory mechanism of serine protease inhibitors of the serpin superfamily depends heavily on
their structural flexibility, which is controlled in large part by the breach and shutter regions of the central
Ab-sheet. We examined codon usage by the highly conserved residues Ser53 and Ser56 of the shutter region
and found a TCN-AGY usage dichotomy for Ser56 that, remarkably, is linked to the
protostome-deuterostome split. Our results suggest that serpin evolution was driven by phylogenetic speciation
and not pressure to fulfill new physiologic functions, mitigating against coevolution with the family of serine
proteases they inhibit.

PMID: 12847097 [PubMed - as supplied by publisher]
J Biol Chem 2002 Oct 25;277(43):40260-4
                                                                                    Related Articles, Links

                 Ser(214) is crucial for substrate binding to serine proteases.

                 Krem MM, Prasad S, Di Cera E.

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis,
                 MO 63110, USA.

Highly conserved amino acids that form crucial structural elements of the catalytic apparatus can be used to
account for the evolutionary history of serine proteases and the cascades into which they are organized. One
such evolutionary marker in chymotrypsin-like proteases is Ser(214), located adjacent to the active site and
forming part of the primary specificity pocket. Here we report the mutation of Ser(214) in thrombin to Ala,
Thr, Cys, Asp, Glu, and Lys. None of the mutants seriously compromises active site catalytic function as
measured by the kinetic parameter k(cat). However, the least conservative mutations result in large increases
in K(m) because of lower rates of substrate diffusion into the active site. Therefore, the role of Ser(214) is to
promote the productive formation of the enzyme-substrate complex. The S214C mutant is catalytically
inactive, which suggests that during evolution the TCN-->AGY codon transitions for Ser(214) occurred
through Thr intermediates.

PMID: 12181318 [PubMed - indexed for MEDLINE]
Trends Biochem Sci 2002 Feb;27(2):67-74
                                                                                    Related Articles, Links

Evolution of enzyme cascades from embryonic development to blood coagulation.

                 Krem MM, Cera ED.

                 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box
                 8231, St Louis, MO 63110-1093, USA.

Recent delineation of the serine protease cascade controlling dorsal-ventral patterning during Drosophila
embryogenesis allows this cascade to be compared with those controlling clotting and complement in
vertebrates and invertebrates. The identification of discrete markers of serine protease evolution has made it
possible to reconstruct the probable chronology of enzyme evolution and to gain new insights into functional
linkages among the cascades. Here, it is proposed that a single ancestral developmental/immunity cascade gave
rise to the protostome and deuterostome developmental, clotting and complement cascades. Extensive
similarities suggest that these cascades were built by adding enzymes from the bottom of the cascade up and
from similar macromolecular building blocks.

                 Publication Types:
                     Review, Tutorial
PMID: 11852243 [PubMed - indexed for MEDLINE]


J Biol Chem. 2002 May 31;277(22):19243-6. Epub 2002 Mar 29.
                                               Related Articles, Links
Substrate recognition drives the evolution of serine proteases.

Rose T, Di Cera E.

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis,
Missouri 63110, USA.

A method is introduced to identify amino acid residues that dictate the functional diversity acquired during
evolution in a protein family. Using over 80 enzymes of the chymotrypsin family, we demonstrate that the
general organization of the phylogenetic tree and its functional branch points are fully accounted for by a
limited number of residues that cluster around the active site of the protein and define the contact region with
the P1-P4 residues of substrate.

PMID: 11925426 [PubMed - indexed for MEDLINE]
Trends Microbiol 2000 May;8(5):238-44
  The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis.

                 Av-Gay Y, Everett M.

                 Divn of Infectious Diseases, University of British Columbia, 2733 Heather St, Vancouver, BC, Canada.

In bacteria, extracellular signals are generally transduced into cellular responses via a two-component system.
However, genome sequence data have now revealed the presence of 'eukaryotic-like' protein kinases and
phosphatases. Mycobacterium tuberculosis appears to be unique among bacteria in that its genome contains 11
members of a newly identified protein kinase family. These M. tuberculosis eukaryotic-like protein kinases
could be key regulators of metabolic processes, including transcription, cell development and interactions with
host cells.

   Publication Types:
                     Review, Tutorial

   PMID: 10785641 [PubMed - indexed for MEDLINE]
EMBO J 2002 Dec 1;21(23):6330-6337
                                                                                    Related Articles, Links
A serpin mutant links Toll activation to melanization in the host defence of Drosophila.

Ligoxygakis P, Pelte N, Ji C, Leclerc V, Duvic B, Belvin M, Jiang H, Hoffmann JA, Reichhart JM.

                  Corresponding author e-mail:
P.Ligoxygakis and N.Pelte contributed equally to this work

A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of
which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the
systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll
receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not
been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization
with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll
pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies
deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its
removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction

  PMID: 12456640 [PubMed - as supplied by publisher]

Int J Biochem Cell Biol. 2003 Nov;35(11):1536-47.
Serpins: structure, function and molecular evolution.

van Gent D, Sharp P, Morgan K, Kalsheker N.

Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, NG7
2UH, Nottingham, UK

The superfamily of serine proteinase inhibitors (serpins) are involved in a number of fundamental biological
processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and
tumor suppression and are expressed in a cell-specific manner. The average protein size of a serpin family
member is 350-400 amino acids, but gene structure varies in terms of number and size of exons and introns.
Previous studies of all known serpins identified 16 clades and 10 orphan sequences. Vertebrate serpins can be
conveniently classified into six sub-groups.We provide additional data that updates the phylogenetic analysis in
the context of structural and functional properties of the proteins. From these, we can conclude that the
functional classification of serpins relies on their protein structure and not on sequence similarity.

PMID: 12824063 [PubMed - in process]
J Thromb Haemost. 2003 Jul;1(7):1535-49.
Mechanisms of glycosaminoglycan activation of the serpins in hemostasis.

Huntington JA.

Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge,

Serpins are the predominant protease inhibitors in the higher organisms and are responsible, in humans, for the
control of many highly regulated processes including blood coagulation and fibrinolysis. The serpin inhibitory
mechanism has recently been revealed by the solution of a crystallographic structure of the final
serpin-protease complex. The serpin mechanism, in contrast to the classical lock-and-key mechanism, involves
dramatic conformational change in both the inhibitor and the inhibited protein. The final result is a stable
covalent complex in which the properties of each component are altered so as to allow clearance from the
circulation. Several serpins are involved in hemostasis: antithrombin (AT) inhibits many coagulation proteases,
most importantly factor Xa and thrombin; heparin cofactor II (HCII) inhibits thrombin; protein C inhibitor
(PCI) inhibits activated protein C and thrombin bound to thrombomodulin; plasminogen activator inhibitor 1
inhibits tissue plasminogen activator; and alpha2-antiplasmin inhibits plasmin. Nearly all of these reactions are
accelerated through interactions with glycosaminoglycans (GAGs) such as heparin or heparan sulfate. Recent
structures of AT, HCII and PCI have revealed how in each case the serpin mechanism has been fine-tuned by
evolution to bring about high levels of regulatory control, and how seemingly disparate mechanisms of GAG
binding and activation can share critical elements. By considering the serpins involved in hemostasis together it
is possible to develop a deeper understanding of their complex individual roles.

PMID: 12871289 [PubMed - in process]

J Thromb Haemost. 2003 Jul;1(7):1343-8.
Inflammation and thrombosis.

Esmon CT.

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation; Departments of
Pathology, and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center; and
Howard Hughes Medical Institute, Oklahoma City, Oklahoma, USA.

Systemic inflammation is a potent prothrombotic stimulus. Inflammatory mechanisms upregulate procoagulant
factors, downregulate natural anticoagulants and inhibit fibrinolytic activity. In addition to modulating plasma
coagulation mechanisms, inflammatory mediators appear to increase platelet reactivity. In vivo, however,
natural anticoagulants not only prevent thrombosis, but they also dampen inflammatory activity. Some insights
into the evolution and linkages between inflammatory mechanisms and the coagulation/anticoagulation
mechanisms have become evident from recent structural studies. This review will summarize the interactions
between inflammation and coagulation.

PMID: 12871267 [PubMed - in process]

  23 replies since Dec. 17 2002,18:45 < Next Oldest | Next Newest >  


Track this topic Email this topic Print this topic

[ Read the Board Rules ] | [Useful Links] | [Evolving Designs]