Tài liệu Báo cáo khoa học: Crystal structure of the catalytic domain of DESC1, a new member of the

Crystal structure of the catalytic domain of DESC1, a new

member of the type II transmembrane serine proteinase

family

Otto J. P. Kyrieleis1,*, Robert Huber1,2, Edgar Ong3

, Ryan Oehler3

, Mike Hunter3

,

Edwin L. Madison3 and Uwe Jacob1,

1 Max-Planck-Institut fu¨r Biochemie, Martinsried, Germany

2 Cardiff University, UK

3 Corvas International, San Diego, CA, USA

DESC1 is a type II transmembrane serine proteinase

(TTSP), an expanding protein family with members

differentially expressed in several organs and certain

tumors. To date, more than 30 mammalian members of

this group have been identified and have, according to

their sequence similarity, been grouped into four sub￾families: DESC ⁄ human airway trypsin (HAT)⁄ HAT￾like type (DESC1–3, HAT, HAT-like 4); matriptase

Keywords

squamous cell carcinoma of the head and

neck; trypsin-like serine protease; tumor

marker; type II transmembrane serine

proteinases

Correspondence

O. J. P. Kyrieleis, Max-Planck-Institut fu¨r

Biochemie, Abteilung Strukturforschung,

Am Klopferspitz 18a, D-82152 Martinsried,

Germany

Fax: +33 0476207199

Tel: +33 0476207860

E-mail: [email protected]

Present address

*EMBL Grenoble Outstation, France

SuppreMol GmbH, Martinsried, Germany

Database

The coordinates and structure factors for

DESC1–benzamidine complex have been

deposited in the RCSB Protein Data Bank

under the accession number 2OQ5

(Received 17 October 2006, revised 31

January 2007, accepted 26 February 2007)

doi:10.1111/j.1742-4658.2007.05756.x

DESC1 was identified using gene-expression analysis between squamous

cell carcinoma of the head and neck and normal tissue. It belongs to the

type II transmembrane multidomain serine proteinases (TTSPs), an

expanding family of serine proteinases, whose members are differentially

expressed in several tissues. The biological role of these proteins is cur￾rently under investigation, although in some cases their participation in

specific functions has been reported. This is the case for enteropeptidase,

hepsin, matriptase and corin. Some members, including DESC1, are associ￾ated with cell differentiation and have been described as tumor markers.

TTSPs belong to the type II transmembrane proteins that display, in addi￾tion to a C-terminal trypsin-like serine proteinase domain, a differing set of

stem domains, a transmembrane segment and a short N-terminal cytoplas￾mic region. Based on sequence analysis, the TTSP family is subdivided into

four subfamilies: hepsin ⁄transmembrane proteinase, serine (TMPRSS);

matriptase; corin; and the human airway trypsin (HAT)⁄ HAT-like ⁄ DESC

subfamily. Members of the hepsin and matriptase subfamilies are known

structurally and here we present the crystal structure of DESC1 as a first

member of the HAT⁄ HAT-like ⁄ DESC subfamily in complex with benza￾midine. The proteinase domain of DESC1 exhibits a trypsin-like serine pro￾teinase fold with a thrombin-like S1 pocket, a urokinase-type plasminogen

activator-type S2 pocket, to accept small residues, and an open hydro￾phobic S3 ⁄ S4 cavity to accept large hydrophobic residues. The deduced

substrate specificity for DESC1 differs markedly from that of other struc￾turally known TTSPs. Based on surface analysis, we propose a rigid

domain association for the N-terminal SEA domain with the back site of

the proteinase domain.

Abbreviations

HAI, hepatocyte growth factor activator inhibitor; HAT, human airway trypsin; PAI-1, plasminogen activator inhibitor 1; PCI, protein C

inhibitor; SRCR, scavenger receptor cystein-rich; TMPRSS, transmembrane proteinase, serine; TTSP, type II transmembrane serine

proteases; uPA, urokinase-type plasminogen activator.

2148 FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS