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J. Biol. Chem., Vol. 280, Issue 23, 22270-22277, June 10, 2005

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Modeling and Experimental Validation of the Binary Complex of the Plectin Actin-binding Domain and the First Pair of Fibronectin Type III (FNIII) Domains of the 4 Integrin^*

Sandy H. M. Litjens, Kevin Wilhelmsen, José M. de Pereda¶, Anastassis Perrakis||, and Arnoud Sonnenberg**

From the Divisions of Cell Biology, and ^||Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands and the Centro de Investigacion del Cancer, University of Salamanca-CSIC, E-37007 Salamanca, Spain

The binding of plectin to the 4 subunit of the 64 integrin is a critical step in the formation of hemidesmosomes. An important interaction between these two proteins occurs between the actin-binding domain (ABD) of plectin and the first pair of fibronectin type III (FNIII) domains and a small part of the connecting segment of 4. Previously, a few amino acids, critical for this interaction, were identified in both plectin and 4 and mapped on the crystal structures of the ABD of plectin and the first pair of FNIII domains of 4. In the present study, we used this biochemical information and protein-protein docking calculations to construct a model of the binary complex between these two protein domains. The top scoring computational model predicts that the calponin-homology 1 (CH1) domain of the ABD associates with the first and the second FNIII domains of 4. Our mutational analysis of the residues at the proposed interface of both the FNIII and the CH1 domains is in agreement with the suggested interaction model. Computational simulations to predict protein motions suggest that the exact model of FNIII and plectin CH1 interaction might well differ in detail from the suggested model due to the conformational plasticity of the FNIII domains, which might lead to a closely related but different mode of interaction with the plectin-ABD. Furthermore, we show that Ser-1325 in the connecting segment of 4 appears to be essential for the recruitment of plectin into hemidesmosomes in vivo. This is consistent with the proposed model and previously published mutational data. In conclusion, our data support a model in which the CH1 domain of the plectin-ABD associates with the groove between the two FNIII domains of 4.

Received for publication, October 18, 2004 , and in revised form, March 11, 2005.

^* This work was supported by Grant NKI 99-2039 from the Dutch Cancer Society (to A. S.) and by Grant SAI2003-02509 from the Spanish Ministry of Education and Science (to J. d. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ An investigator of the Ramón y Cajal Program (Spanish Ministry of Education and Science).

^** To whom correspondence should be addressed. Tel.: 31-20-512-1942; Fax: 31-20-512-1944; E-mail: a.sonnenberg{at}nki.nl.

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