C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking

PLoS One. 2011;6(6):e21023. doi: 10.1371/journal.pone.0021023. Epub 2011 Jun 15.

Abstract

Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / chemistry
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Line
  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Progranulins
  • Protein Binding
  • Protein Transport
  • Sequence Homology, Amino Acid

Substances

  • Adaptor Proteins, Vesicular Transport
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • sortilin