| Structural highlights
Function
SP2_ANOGA Serine protease inhibitor that functions in the melanization-mediated immune response (PubMed:16113656, PubMed:20953892, PubMed:21465556, PubMed:25525260, PubMed:33045027, PubMed:33520733). By preventing the activation of phenoloxidases through the inhibiting of serine proteases CLIPB9, CLIPB10 and CLIPB4, negatively regulates melanization in the hemolymph (PubMed:16113656, PubMed:20953892, PubMed:21465556, PubMed:25525260, PubMed:33045027, PubMed:33520733, PubMed:37703846). By preventing melanization, has a detrimental role during P.berghei parasite mediated-infection and invasion of the mosquito midgut (PubMed:16113656).[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Serpin-2 (SRPN2) is a key negative regulator of the melanization response in the malaria vector Anopheles gambiae. SRPN2 irreversibly inhibits clip domain serine proteinase 9 (CLIPB9), which functions in a serine proteinase cascade culminating in the activation of prophenoloxidase and melanization. Silencing of SRPN2 in A. gambiae results in spontaneous melanization and decreased life span and is therefore a promising target for vector control. The previously determined structure of SRPN2 revealed a partial insertion of the hinge region of the reactive center loop (RCL) into beta sheet A. This partial hinge insertion participates in heparin-linked activation in other serpins, notably antithrombin III. SRPN2 does not contain a heparin binding site, and any possible mechanistic function of the hinge insertion was previously unknown. To investigate the function of the SRPN2 hinge insertion, we developed three SRPN2 variants in which the hinge regions are either constitutively expelled or inserted and analyzed their structure, thermostability, and inhibitory activity. We determined that constitutive hinge expulsion resulted in a 2.7-fold increase in the rate of CLIPB9Xa inhibition, which is significantly lower than previous observations of allosteric serpin activation. Furthermore, we determined that stable insertion of the hinge region did not appreciably decrease the accessibility of the RCL to CLIPB9. Together, these results indicate that the partial hinge insertion in SRPN2 does not participate in the allosteric activation observed in other serpins and instead represents a molecular trade-off between RCL accessibility and efficient formation of an inhibitory complex with the cognate proteinase.
Structural and Inhibitory Effects of Hinge Loop Mutagenesis in Serpin-2 from the Malaria Vector Anopheles gambiae.,Zhang X, Meekins DA, An C, Zolkiewski M, Battaile KP, Kanost MR, Lovell S, Michel K J Biol Chem. 2015 Jan 30;290(5):2946-56. doi: 10.1074/jbc.M114.625665. Epub 2014 , Dec 17. PMID:25525260[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Michel K, Budd A, Pinto S, Gibson TJ, Kafatos FC. Anopheles gambiae SRPN2 facilitates midgut invasion by the malaria parasite Plasmodium berghei. EMBO Rep. 2005 Sep;6(9):891-7. PMID:16113656 doi:10.1038/sj.embor.7400478
- ↑ An C, Budd A, Kanost MR, Michel K. Characterization of a regulatory unit that controls melanization and affects longevity of mosquitoes. Cell Mol Life Sci. 2011 Jun;68(11):1929-39. PMID:20953892 doi:10.1007/s00018-010-0543-z
- ↑ An C, Lovell S, Kanost MR, Battaile KP, Michel K. Crystal structure of native Anopheles gambiae serpin-2, a negative regulator of melanization in mosquitoes. Proteins. 2011 Feb 3. doi: 10.1002/prot.23002. PMID:21465556 doi:10.1002/prot.23002
- ↑ Zhang X, Meekins DA, An C, Zolkiewski M, Battaile KP, Kanost MR, Lovell S, Michel K. Structural and Inhibitory Effects of Hinge Loop Mutagenesis in Serpin-2 from the Malaria Vector Anopheles gambiae. J Biol Chem. 2015 Jan 30;290(5):2946-56. doi: 10.1074/jbc.M114.625665. Epub 2014 , Dec 17. PMID:25525260 doi:http://dx.doi.org/10.1074/jbc.M114.625665
- ↑ Sousa GL, Bishnoi R, Baxter RHG, Povelones M. The CLIP-domain serine protease CLIPC9 regulates melanization downstream of SPCLIP1, CLIPA8, and CLIPA28 in the malaria vector Anopheles gambiae. PLoS Pathog. 2020 Oct 12;16(10):e1008985. PMID:33045027 doi:10.1371/journal.ppat.1008985
- ↑ Zhang X, Li M, El Moussawi L, Saab S, Zhang S, Osta MA, Michel K. CLIPB10 is a Terminal Protease in the Regulatory Network That Controls Melanization in the African Malaria Mosquito Anopheles gambiae. Front Cell Infect Microbiol. 2021 Jan 15;10:585986. PMID:33520733 doi:10.3389/fcimb.2020.585986
- ↑ Zhang X, Zhang S, Kuang J, Sellens KA, Morejon B, Saab SA, Li M, Metto EC, An C, Culbertson CT, Osta MA, Scoglio C, Michel K. CLIPB4 Is a Central Node in the Protease Network that Regulates Humoral Immunity in Anopheles gambiae Mosquitoes. J Innate Immun. 2023;15(1):680-696. PMID:37703846 doi:10.1159/000533898
- ↑ Zhang X, Meekins DA, An C, Zolkiewski M, Battaile KP, Kanost MR, Lovell S, Michel K. Structural and Inhibitory Effects of Hinge Loop Mutagenesis in Serpin-2 from the Malaria Vector Anopheles gambiae. J Biol Chem. 2015 Jan 30;290(5):2946-56. doi: 10.1074/jbc.M114.625665. Epub 2014 , Dec 17. PMID:25525260 doi:http://dx.doi.org/10.1074/jbc.M114.625665
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