PDBsum entry 6e4z

Immune system

PDB id: 6e4z

Contents

Protein chains

210 a.a.

218 a.a.

15 a.a.

Ligands

SO4

Metals

_ZN ×5

Waters ×122

PDB id:

6e4z

Name:

Immune system

Title:

Anti-pcsk9 fab 6e2 bound to the modified n-terminal peptide from pcsk9

Structure:

6e2 heavy chain. Chain: h. Fragment: fab. Engineered: yes. 6e2 light chain. Chain: l. Fragment: fab. Engineered: yes. Proprotein convertase subtilisin/kexin type 9.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606

Resolution:

2.20Å R-factor: 0.197 R-free: 0.236

Authors:

M.H.Ultsch,D.K.Kirchhofer

Key ref:

M.Ultsch et al. (2019). Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain. J Mol Biol, 431, 885-903. PubMed id: 30653992 DOI: 10.1016/j.jmb.2018.11.025

Date:

18-Jul-18 Release date: 10-Apr-19

Protein chain

No UniProt id for this chain

Struc: 210 a.a.

Protein chain

A0A097PUG4  (A0A097PUG4_MOUSE) -  Anti-lox-1 15C4 light chain from Mus musculus

Seq: 238 a.a.

Struc: 218 a.a.*

Protein chain

Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9 from Homo sapiens

Seq: 692 a.a.

Struc: 15 a.a.*

* PDB and UniProt seqs differ at 48 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chain L: E.C.?
• Enzyme class 3: Chain P: E.C.3.4.21.- - ?????

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

DOI no: 10.1016/j.jmb.2018.11.025

J Mol Biol 431:885-903 (2019)

PubMed id: 30653992

Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain.

M.Ultsch, W.Li, C.Eigenbrot, P.Di Lello, M.T.Lipari, S.Gerhardy, A.P.AhYoung, J.Quinn, Y.Franke, Y.Chen, M.Kong Beltran, A.Peterson, D.Kirchhofer.

ABSTRACT

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipid metabolism by degrading liver LDL receptors. Structural studies have provided molecular details of PCSK9 function. However, the N-terminal acidic stretch of the PCSK9 prodomain (Q31-T60) has eluded structural investigation, since it is in a disordered state. The interest in this region is intensified by the presence of human missense mutations associated with low and high LDL-c levels (E32K, D35Y, and R46L, respectively), as well as two posttranslationally modified sites, sulfated Y38 and phosphorylated S47. Herein we show that a segment within this region undergoes disorder-to-order transition. Experiments with acidic stretch-derived peptides demonstrated that the folding is centered at the segment Y38-L45, which adopts an α-helix as determined by NMR analysis of free peptides and by X-ray crystallography of peptides in complex with antibody 6E2 (Ab6E2). In the Fab6E2-peptide complexes, the structured region features a central 2 1/4-turn α-helix and encompasses up to 2/3 of the length of the acidic stretch, including the missense mutations and posttranslationally modified sites. Experiments with helix-breaking proline substitutions in peptides and in PCSK9 protein indicated that Ab6E2 specifically recognizes the helical conformation of the acidic stretch. Therefore, the observed quantitative binding of Ab6E2 to native PCSK9 from various cell lines suggests that the disorder-to-order transition is a true feature of PCSK9 and not limited to peptides. Because the helix provides a constrained spatial orientation of the missense mutations and the posttranslationally modified residues, it is probable that their biological functions take place in the context of an ordered conformational state.