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Sorting It All Out: Signal-mediated Protein Trafficking in the Endosomal-Lysosomal System

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Published on Nov 15, 2010

Air date: Thursday, December 03, 2009, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
Category: Wednesday Afternoon Lectures
Description: The interior of eukaryotic cells is organized into an array of membrane-bound compartments. Each of these compartments has a characteristic protein composition that is responsible for its specific function. My laboratory has been interested in the molecular mechanisms that determine protein localization to different intracellular compartments, with a particular focus on organelles that make up the endosomal-lysosomal system. This system comprises various types of endosome (e.g., early, late, recycling), lysosomes and a family of "lysosome-related organelles" (LROs) (e.g., melanosomes, platelet dense bodies, cytotoxic granules, etc.), as well as the trans-Golgi network (TGN) and domains of the plasma membrane, which feed into this system. We have found that delivery of transmembrane proteins to these compartments is mediated by an elaborate system of sorting signals and adaptor proteins. Endosomal-lysosomal sorting signals generally occur within the cytosolic domains of transmembrane proteins and consist of linear arrays of amino acids that fit one of several consensus motifs. These include different types of "tyrosine-based" and "dileucine-based" sorting signals, so named on the basis of the most conserved and critical amino acids in the signal. These signals function as "bar codes" that are decoded by adaptors such as the AP-1, AP-2, AP-3 and AP-4 heterotetrameric complexes, the monomeric GGA1, GGA2, and GGA3 proteins, and several others, all of which are components of protein coats associated with the cytosolic face of membranes (e.g., clathrin coats). Signal-adaptor interactions result in incorporation of transmembrane cargoes into coated transport carriers destined to different organelles of the endosomal-lysosomal system. Understanding the mechanisms of protein sorting in this system is key to the elucidation of the pathogenesis of various genetic disorders caused by mutations in the signals (e.g., some forms of familial hypercholesterolemia) or the adaptors (e.g., Hermansky-Pudlak syndrome type 2), or by their exploitation by intracellular pathogens such as viruses and bacteria. Over the years we have discovered and characterized various sorting signals and adaptors, and examined their involvement in several pathologies. We have recently found that the heterotetrameric AP-4 complex plays a role in the intracellular trafficking and processing of the Alzheimer's Disease (AD) amyloid precursor protein (APP). An interaction screen showed that a previously unknown signal in the cytosolic tail of APP binds to the mu4 subunit of AP-4. The biochemical and structural details of this interaction are distinct from others that have been characterized to date. Mutation of the signal or depletion of cellular mu4 shift the steady-state localization of APP from endosomes to the TGN, and enhance amyloidogenic processing of APP to the pathogenic amyloid-beta (Abeta) peptide. These findings indicate that AP-4 sorts APP from the TGN to endosomes, and that amyloidogenic processing of APP is favored by localization to the TGN or the late secretory pathway. Thus, AP-4 exerts a protective effect that guards against excessive Abeta production. Defective expression of AP-4 should therefore be considered a potential risk factor for AD.

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
Runtime: 00:59:28

Series: NIH director's Wednesday afternoon lecture series
Author: Bonifacino, Juan S.
National Institutes of Health (U.S.)
Publisher: [Bethesda, Md. : National Institutes of Health, 2009]
Permanent link: http://videocast.nih.gov/launch.asp?1...

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