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Structural determinants involved in the regulation of CXCL14/BRAK expression by the 26 S proteasome. J Mol Biol 2006 Nov 03;363(4):813-22

Date

09/22/2006

Pubmed ID

16987528

Pubmed Central ID

PMC1664593

DOI

10.1016/j.jmb.2006.08.057

Scopus ID

2-s2.0-33749637220   30 Citations

Abstract

The chemokine CXCL14/BRAK participates in immune surveillance by recruiting dendritic cells. CXCL14 gene expression is altered in a number of cancers, but protein expression levels have not been investigated. Here we report that CXCL14 protein can be expressed in primary epithelial cells; however, in several immortalized and cancer cell lines this protein is targeted for polyubiquitylation and proteasomal degradation. We determined the NMR structure of CXCL14 to identify motifs controlling its expression. CXCL14 adopts the canonical chemokine tertiary fold but contains a unique five amino acid insertion (41VSRYR45) relative to other CXC chemokines. Deletion or substitution of key residues within this insertion prevented proteasomal degradation. Furthermore, we defined a 15 amino acid fragment of CXCL14 that is sufficient to induce proteasomal degradation. This study elucidates a post-translational mechanism for the loss of CXCL14 in cancer and a novel mode of chemokine regulation.

Author List

Peterson FC, Thorpe JA, Harder AG, Volkman BF, Schwarze SR

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Chemokines, CXC
Enzyme Inhibitors
Humans
Interleukin-8
Molecular Sequence Data
Mutant Proteins
Nuclear Magnetic Resonance, Biomolecular
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Structure, Secondary
Recombinant Fusion Proteins
Structure-Activity Relationship
Tumor Cells, Cultured
jenkins-FCD Prod-461 7d7c6113fc1a2757d2947d29fae5861c878125ab