Pellino proteins contain a non-canonical FHA domain that mediates the interaction with IRAK1.

Format:

Book

Thesis/Dissertation

Author/Creator:

Lin, Chun-Chi.

Contributor:

Ferguson, Kathryn M., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Biophysics.

0786.

Penn dissertations--Biochemistry and molecular biophysics.

Biochemistry and molecular biophysics--Penn dissertations.

Local Subjects:

Penn dissertations--Biochemistry and molecular biophysics.

Biochemistry and molecular biophysics--Penn dissertations.

0786.

Physical Description:

134 pages

Contained In:

Dissertation Abstracts International 70-01B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Our body's initial defense mechanism against hostile microbial invasions is governed by the innate immune system. Toll/Interleukin-1 receptor (TIR) signaling in innate immunity utilizes a variety of protein recognition modules for downstream signaling such as the Toll/Interleukin-1 Receptor (TIR) Domain and the Death Domain. The precise molecular interaction at the upstream signaling events involving a crucial adaptor protein, Pellino, is not understood. Pellino proteins are a family of RING E3 ubiquitin ligases involved in signaling events downstream of the Toll and interleukin-1 (IL-1) receptors, the key initiators of cellular innate immune responses. Pellino proteins associate with and, in some cases, ubiquitinate a number of proteins in these pathways, including the interleukin-1 receptor associated kinase 1 (IRAK1). This study determined the high resolution X-ray crystal structure of the Pellino2 N-terminal region, and found that it consists largely of a previously unidentified FHA domain. FHA domains are well-characterized phosphothreonine-binding modules, and the cryptic example that this study has found in Pellino2 can drive the interaction of this protein with phosphorylated IRAK1. The Pellino FHA domain is decorated with an unusual appendage or 'wing' composed of two long inserts that impede identification of the FHA domain on the basis of amino acid homology alone. The Pellino N-terminal FHA domain alone is sufficient to mediate the interaction with IRAK1 and a phosphopeptide using pull-down studies. Alteration of amino acids in the conserved FHA phosphothreonine-binding site abolishes the interaction of Pellino2 with phosphorylated IRAK1. In addition, dephosphorylation of IRAK1 prevents the interaction with Pellino2. Surface analysis of the Pellino FHA domain suggests that it may bind to phosphorylated IRAK1 through two or more phosphothreonines and that the wing may also contain important IRAK1 interaction surfaces. Delineating how this RING E3 ubiquitin ligase associate with its substrates, and how these interactions are regulated by phosphorylation is crucial for a complete understanding of TIR signaling.

Notes:

Thesis (Ph.D. in Biochemistry and Molecular Biophysics) -- University of Pennsylvania, 2008.

Source: Dissertation Abstracts International, Volume: 70-01, Section: B, page: 0153.

Adviser: Kathryn M. Ferguson.

Local Notes:

School code: 0175.

ISBN:

9781109008289

Access Restriction:

Restricted for use by site license.