PDBsum entry 4wrn

Structural protein

PDB id: 4wrn

Contents

Protein chains

693 a.a.

Ligands

GLC-GLC ×2

NAG ×3

Metals

_ZN ×2

PDB id:

4wrn

Name:

Structural protein

Title:

Crystal structure of the polymerization region of human uromodulin/tamm-horsfall protein

Structure:

Maltose-binding periplasmic protein,uromodulin. Chain: a, b. Synonym: mbp,mmbp,maltodextrin-binding protein,tamm-horsfall urinary glycoprotein,thp. Engineered: yes. Mutation: yes. Other_details: this protein is a chimera. Residues 25-391 are from e. Coli maltose binding protein (mbp), correspond to residues 27-393 of swiss-prot database entry p0aex9 and contain mutations i26t, d106a,

Source:

Escherichia coli o157:h7, homo sapiens. Human. Organism_taxid: 83334, 9606. Gene: male, z5632, ecs5017, umod. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s. Expression_system_atcc_number: crl-3022.

Resolution:

3.20Å R-factor: 0.222 R-free: 0.246

Authors:

M.Bokhove,D.De Sanctis,L.Jovine

Key ref:

M.Bokhove et al. (2016). A structured interdomain linker directs self-polymerization of human uromodulin. Proc Natl Acad Sci U S A, 113, 1552-1557. PubMed id: 26811476 DOI: 10.1073/pnas.1519803113

Date:

24-Oct-14 Release date: 27-Jan-16

Protein chains

P07911  (UROM_HUMAN) -  Uromodulin from Homo sapiens

Seq: 640 a.a.

Struc: 693 a.a.*

Protein chains

P0AEY0  (MALE_ECO57) -  Maltose/maltodextrin-binding periplasmic protein from Escherichia coli O157:H7

Seq: 396 a.a.

Struc: 693 a.a.*

* PDB and UniProt seqs differ at 310 residue positions (black crosses)

DOI no: 10.1073/pnas.1519803113

Proc Natl Acad Sci U S A 113:1552-1557 (2016)

PubMed id: 26811476

A structured interdomain linker directs self-polymerization of human uromodulin.

M.Bokhove, K.Nishimura, M.Brunati, L.Han, D.de Sanctis, L.Rampoldi, L.Jovine.

ABSTRACT

Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, salt-dependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins α-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes.