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3ndd

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Revision as of 06:42, 7 August 2019

Cleaved antitrypsin with P10 Pro, and P9-P6 Asp

Structural highlights

3ndd is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	3ndf
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[A1AT_HUMAN] Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490]. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.^[1] ^[2] ^[3]

Function

[A1AT_HUMAN] Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:]^[4] ^[5] Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:]^[6] ^[7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The serpin mechanism of protease inhibition involves the rapid and stable incorporation of the reactive center loop (RCL) into central beta-sheet A. Serpins therefore require a folding mechanism that bypasses the most stable "loop-inserted" conformation to trap the RCL in an exposed and metastable state. This unusual feature of serpins renders them highly susceptible to point mutations that lead to the accumulation of hyperstable misfolded polymers in the endoplasmic reticulum of secretory cells. The ordered and stable protomer-protomer association in serpin polymers has led to the acceptance of the "loop-sheet" hypothesis of polymerization, where a portion of the RCL of one protomer incorporates in register into sheet A of another. Although this mechanism was proposed 20 years ago, no study has ever been conducted to test its validity. Here, we describe the properties of a variant of alpha(1)-antitrypsin with a critical hydrophobic section of the RCL substituted with aspartic acid (P8-P6). In contrast to the control, the variant was unable to polymerize when incubated with small peptides or when cleaved in the middle of the RCL (accepted models of loop-sheet polymerization). However, when induced by guanidine HCl or heat, the variant polymerized in a manner indistinguishable from the control. Importantly, the Asp mutations did not affect the ability of the Z or Siiyama alpha(1)-antitrypsin variants to polymerize in COS-7 cells. These results argue strongly against the loop-sheet hypothesis and suggest that, in serpin polymers, the P8-P6 region is only a small part of an extensive domain swap.

Loop-sheet mechanism of serpin polymerization tested by reactive center loop mutations.,Yamasaki M, Sendall TJ, Harris LE, Lewis GM, Huntington JA J Biol Chem. 2010 Oct 1;285(40):30752-8. Epub 2010 Jul 28. PMID:20667823^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Seyama K, Nukiwa T, Takabe K, Takahashi H, Miyake K, Kira S. Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)). A new alpha 1-antitrypsin-deficient variant with mutation on a predicted conserved residue of the serpin backbone. J Biol Chem. 1991 Jul 5;266(19):12627-32. PMID:1905728
↑ Holmes MD, Brantly ML, Fells GA, Crystal RG. Alpha 1-antitrypsin Wbethesda: molecular basis of an unusual alpha 1-antitrypsin deficiency variant. Biochem Biophys Res Commun. 1990 Aug 16;170(3):1013-20. PMID:2390072
↑ Graham A, Kalsheker NA, Bamforth FJ, Newton CR, Markham AF. Molecular characterisation of two alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) Null(Newport) (Gly115----Ser) and (Pi) Z Wrexham (Ser-19----Leu). Hum Genet. 1990 Oct;85(5):537-40. PMID:2227940
↑ Tanaka N, Sekiya S, Takamizawa H, Kato N, Moriyama Y, Fujimura S. Characterization of a 54 kDa, alpha 1-antitrypsin-like protein isolated from ascitic fluid of an endometrial cancer patient. Jpn J Cancer Res. 1991 Jun;82(6):693-700. PMID:1906855
↑ Niemann MA, Narkates AJ, Miller EJ. Isolation and serine protease inhibitory activity of the 44-residue, C-terminal fragment of alpha 1-antitrypsin from human placenta. Matrix. 1992 Jun;12(3):233-41. PMID:1406456
↑ Tanaka N, Sekiya S, Takamizawa H, Kato N, Moriyama Y, Fujimura S. Characterization of a 54 kDa, alpha 1-antitrypsin-like protein isolated from ascitic fluid of an endometrial cancer patient. Jpn J Cancer Res. 1991 Jun;82(6):693-700. PMID:1906855
↑ Niemann MA, Narkates AJ, Miller EJ. Isolation and serine protease inhibitory activity of the 44-residue, C-terminal fragment of alpha 1-antitrypsin from human placenta. Matrix. 1992 Jun;12(3):233-41. PMID:1406456
↑ Yamasaki M, Sendall TJ, Harris LE, Lewis GM, Huntington JA. Loop-sheet mechanism of serpin polymerization tested by reactive center loop mutations. J Biol Chem. 2010 Oct 1;285(40):30752-8. Epub 2010 Jul 28. PMID:20667823 doi:10.1074/jbc.M110.156042

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ndd"

@@ Line 1: / Line 1: @@
 ==Cleaved antitrypsin with P10 Pro, and P9-P6 Asp==
-<StructureSection load='3ndd' size='340' side='right' caption='[[3ndd]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
+<StructureSection load='3ndd' size='340' side='right'caption='[[3ndd]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3ndd]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NDD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NDD FirstGlance]. <br>
@@ Line 15: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nd/3ndd_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nd/3ndd_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 30: / Line 30: @@
 </div>
 <div class="pdbe-citations 3ndd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Alpha-1-antitrypsin 3D structures|Alpha-1-antitrypsin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Huntington, J A]]
 [[Category: Sendall, T J]]

3ndd

From Proteopedia

Revision as of 06:42, 7 August 2019

Cleaved antitrypsin with P10 Pro, and P9-P6 Asp

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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