PDBsum entry 3io6

Signaling protein

PDB id: 3io6

Contents

Protein chain

400 a.a. *

Metals

_CA ×9

_ZN ×5

* Residue conservation analysis

PDB id:

3io6

Name:

Signaling protein

Title:

Huntingtin amino-terminal region with 17 gln residues - crystal c92-a

Structure:

Maltose-binding periplasmic protein, huntingtin fusion protein. Chain: a, c, b. Fragment: fusion protein, see remark 999. Synonym: mmbp, maltodextrin-binding protein, huntington disease protein, hd protein. Engineered: yes

Source:

Escherichia coli k-12, homo sapiens. Bacteria, human. Organism_taxid: 83333, 9606. Strain: k12. Gene: male, b4034, jw3994, htt, hd, it15. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

3.70Å R-factor: 0.248 R-free: 0.293

Authors:

M.W.Kim,Y.Chelliah,S.W.Kim,Z.Otwinowski,I.Bezprozvanny

Key ref:

M.W.Kim et al. (2009). Secondary structure of Huntingtin amino-terminal region. Structure, 17, 1205-1212. PubMed id: 19748341 DOI: 10.1016/j.str.2009.08.002

Date:

13-Aug-09 Release date: 27-Oct-09

Protein chains

P0AEX9  (MALE_ECOLI) -  Maltose/maltodextrin-binding periplasmic protein from Escherichia coli (strain K12)

Seq: 396 a.a.

Struc: 400 a.a.*

Protein chains

P42858  (HD_HUMAN) -  Huntingtin from Homo sapiens

Seq: 3142 a.a.

Struc: 400 a.a.

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.str.2009.08.002

Structure 17:1205-1212 (2009)

PubMed id: 19748341

Secondary structure of Huntingtin amino-terminal region.

M.W.Kim, Y.Chelliah, S.W.Kim, Z.Otwinowski, I.Bezprozvanny.

ABSTRACT

Huntington's disease is a genetic neurodegenerative disorder resulting from polyglutamine (polyQ) expansion (>36Q) within the first exon of Huntingtin (Htt) protein. We applied X-ray crystallography to determine the secondary structure of the first exon (EX1) of Htt17Q. The structure of Htt17Q-EX1 consists of an amino-terminal alpha helix, poly17Q region, and polyproline helix formed by the proline-rich region. The poly17Q region adopts multiple conformations in the structure, including alpha helix, random coil, and extended loop. The conformation of the poly17Q region is influenced by the conformation of neighboring protein regions, demonstrating the importance of the native protein context. We propose that the conformational flexibility of the polyQ region observed in our structure is a common characteristic of many amyloidogenic proteins. We further propose that the pathogenic polyQ expansion in the Htt protein increases the length of the random coil, which promotes aggregation and facilitates abnormal interactions with other proteins in cells.

Selected figure(s)

Figure 1.
Figure 1. Secondary Structure of Htt17Q-EX1
(A) Amino acid sequence of MBP-Htt17Q-EX1. MBP3A denotes the maltose binding protein followed by a 3Ala linker. M371 to Q430 is the sequence of Htt17Q-EX1, which is subdivided into a 17 aa N-terminal region (M371 to F387), poly17Q region (Q388 to Q404), poly11P region (P405 to P415), and 15 aa mixed P/Q region (Q416 to Q430). The sequence from Q431 to the C terminus is the 19 aa tag added to facilitate crystallization.
(B) The structure of Htt17Q-EX1 trimer from c^95 crystal. The structures of MBP and 3A linker are removed for clarity. The amino-terminal α helix of Htt17Q-EX1 extends from Met371 to Phe387 (Green). The following poly17Q region (orange) is α helical and unstructured (random coil). The poly11P region (blue) adopts a PP helix (shown as stick model) in the kinked conformation. The initial part of the polyP/Q region (purple) is also in PP-helix conformation (shown as stick model). The terminal part of the poly17Q region (orange) is in the extended conformation (shown as stick model).
(C) The structure of Htt17Q-EX1 trimer from c[Hg]^99 crystal. Same as in (B) but the poly11P region is in the straight conformation.
(D) The complete structure of B molecule of Htt17Q-EX1 monomer from c^95 crystal. The striped orange loops are for the random coil region between Gln389 and Gln399, which is invisible on the map.
(E) The complete structure of A molecule of Htt17Q-EX1 monomer from c[Hg]^99 crystal. The striped orange loops are for the random coil region between Gln391 and Gln398, which is invisible on the map.

Figure 2.
Figure 2. Structure of Amino-Terminal and Poly17Q Regions of Htt17Q-EX1
The structures of the amino-terminal region (green) and poly17Q region (orange) of Htt17Q-EX1 are shown for three different molecules with variable lengths of poly17Q α helix. Also shown are corresponding regions of electron density maps contoured at 1.0 σ (blue).
(A) The short poly17Q helix makes a transition to loop at Gln388 (molecule A, crystal c^95).
(B) The medium poly17Q helix makes a transition to loop at Gln395 (molecule C, crystal c^90).
(C) The long poly17Q helix extends for the length of the polyQ region until Gln402 (molecule C, crystal c[Hg]^99).

The above figures are reprinted by permission from Cell Press: Structure (2009, 17, 1205-1212) copyright 2009.

Figures were selected by an automated process.