PDBsum entry 1jjo

Signaling protein

PDB id: 1jjo

Contents

Protein chains

40 a.a. *

244 a.a. *

33 a.a. *

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Crystal structure of neuroserpin: a neuronal serpin involved in a conformational disease.

Authors

C.Briand, S.V.Kozlov, P.Sonderegger, M.G.Grütter.

Ref.

FEBS Lett, 2001, 505, 18-22. [DOI no: 10.1016/S0014-5793(01)02764-8]

PubMed id

11557034

Abstract

The protease inhibitor neuroserpin regulates the development of the nervous system and its plasticity in the adult. Neuroserpins carrying the Ser53Pro or Ser56Arg mutation form polymers in neuronal cells. We describe here the structure of wild-type neuroserpin in a cleaved form. The structure provides a basis to understand the role of the mutations in the polymerization process. We propose that these mutations could delay the insertion of the reactive center loop into the central beta-sheet A, an essential step in the inhibition and possibly in the polymerization of neuroserpin.

Figure 3.
Fig. 3. Ser53 and Ser56 and the insertion of RCL: a model. A: The ‘shutter region’ in the native form (in dark blue, template α1-antitrypsin [27]). A ring of hydrogen bonds links the side chain of Ser56, His334 and Asn186. B: After preinsertion of the RCL (in green), His334 must rotate and interact with the backbone C=O of Asn186. During the preinsertion of the RCL, Val188 slides between Ser53 and Ser56 ( Fig. 4A), so Ser56 must also rotate. Consequently, Asn186 has to rotate to maintain its interaction with Ser56 (antithrombin structure used as a template [26]). C: Asn186 continues to slide between residues 56 and 60 ( Fig. 4A). Its side chain rotates to a similar position as seen in the native form. Ser351 takes the place of Asn186 and the β-strand s3A translocates from its preinserted position to its relaxed position (in orange; structure of neuroserpin). The loss of the hydrogen bond between Asn186 and His334 is compensated for by the formation of a hydrogen bond with the OH side chain of Ser351. Prepared with Setor [31].

Figure 4.
Fig. 4. Effect of the two mutations on the RCL insertion mechanism. A: During the preinsertion (β-strand s3A in blue moved to the position in green) and the full insertion of the RCL (β-strand s3A in orange) Val188 has to slide into groove 1 of α-helix hB (residues 53–56). Likewise, Asn186 has to slide into groove 2 of α-helix hB (residues 56–60). B: Effect of the Ser53Pro mutation. β-Strand s6A and α-helix hB of the cleaved form are colored in orange. By adding a new hydrophobic residue in the native form (in dark blue) and in the preinserted form (in green), Val188 of β-strand s3A can make a hydrophobic interaction with Pro53. After RCL insertion, a rearrangement in the bottom part of β-strand s3A occurs, affecting the position of Val188. Since this hydrophobic interaction must be disrupted after preinsertion to fully insert the RCL, the rate of insertion could be reduced. C: Effect of the Ser56Arg mutation. Arg56 replaces Ser56, which normally swings during the insertion of the reactive loop [28]. Conversely, in the native form and in the preinserted form (here in green) the Nε side chain of Arg56 can hydrogen-bond the Oδ side chain of Asn186. The Nη1 or Nη2 side chain of Arg56 will also hydrogen-bond the Oδ side chain of Asn94. Arg56 is at the place where Asn186 has to slide when the loop is fully inserted. To fully insert the RCL, Arg56 must lose its hydrogen bonds and shift into another position, that is also slowing down the rate of the full insertion. Prepared with Setor [31].

The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS Lett (2001, 505, 18-22) copyright 2001.