PDBsum entry 1s1n

Cell adhesion

PDB id: 1s1n

Contents

Protein chain

60 a.a. *

* Residue conservation analysis

PDB id:

1s1n

Name:

Cell adhesion

Title:

Sh3 domain of human nephrocystin

Structure:

Nephrocystin 1. Chain: a. Fragment: sh3 domain. Synonym: juvenile nephronophthisis 1 protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nphp1, nph1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

NMR struc:

17 models

Authors:

A.Le Maire,T.Weber,S.Saunier,C.Antignac,A.Ducruix,F.Dardel

Key ref:

A.le Maire et al. (2005). Solution NMR structure of the SH3 domain of human nephrocystin and analysis of a mutation-causing juvenile nephronophthisis. Proteins, 59, 347-355. PubMed id: 15723349 DOI: 10.1002/prot.20344

Date:

07-Jan-04 Release date: 18-Jan-05

Protein chain

O15259  (NPHP1_HUMAN) -  Nephrocystin-1 from Homo sapiens

Seq: 732 a.a.

Struc: 60 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1002/prot.20344

Proteins 59:347-355 (2005)

PubMed id: 15723349

Solution NMR structure of the SH3 domain of human nephrocystin and analysis of a mutation-causing juvenile nephronophthisis.

A.le Maire, T.Weber, S.Saunier, I.Broutin, C.Antignac, A.Ducruix, F.Dardel.

ABSTRACT

Human nephrocystin is a protein associated with juvenile NPH, an autosomal recessive, inherited kidney disease responsible for chronic renal failure in children. It contains an SH3 domain involved in signaling pathways controlling cell adhesion and cytoskeleton organization. The solution structure of this domain was solved by triple resonance NMR spectroscopy. Within the core, the structure is similar to those previously reported for other SH3 domains but exhibits a number of specific noncanonical features within the polyproline ligand binding site. Some of the key conserved residues are missing, and the N-Src loop exhibits an unusual twisted geometry, which results in a narrowing of the binding groove. This is induced by the replacement of a conserved Asp, Asn, or Glu residue by a Pro at one side of the N-Src loop. A systematic survey of other SH3 domains also containing a Pro at this position reveals that most of them belong to proteins involved in cell adhesion or motility. A variant of this domain, which carries a point mutation causing NPH, was also analyzed. This change, L180P, although it corresponds to a nonconserved and solvent-exposed position, causes a complete loss of the tertiary structure. Similar effects are also observed with the L180A variant. This could be a context-dependent effect resulting from an interaction between neighboring charged side-chains.

Selected figure(s)

Figure 3.
Figure 3. The N-src loop of nephrocystin SH3 is twisted by a noncanonical proline residue. Stereo view of the superimposed backbones of nephrocystin (green) and N-Crk SH3 (yellow; PDB entry: 1CKA). The two structures are very similar, with the exception of the N-Src loop, at the right. Proline 186, which induces a kink in nephrocystin, is shown in red. It corresponds to a position where a semiconserved Glu, Asp, or Asn residue is found in most SH3 domains.

Figure 5.
Figure 5. Destabilization of the SH3 fold by the L180 mutations. (Left) Sructure of the wild-type nephrocystin SH3. The side-chains of E156, L180, and K193 are indicated. (Right) Model of the mutant L180P structure. The diverging type II -turn, which folds independently in solution is highligthed in yellow. After the MD simulation, the major structural change was the movement of E156 and K193 side-chains, the terminal atoms of which come in Van der Waals contact over the pyrrolidine ring of P180 (right). This also induced a partial disruption of the underlying -sheet structure.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2005, 59, 347-355) copyright 2005.

Figures were selected by the author.