New biology unveiled for the fundamental cellular machinery

Cellular communication relies on receptor molecules on the cell surface. The periodic uptake and sorting of these receptors, critical for their degradation or recycling, are governed by an elaborate machinery, prominently featuring the Commander complex.

Research teams at the Institute of Biotechnology, University of Helsinki, led by Dr. Markku Varjosalo and Prof. Juha Huiskonen dissected the molecular interactions and atomic structure of this supercomplex, in its purest native form present in human cells.

The study is published in Nature Structural and Molecular Biology.

New avenues for potential therapeutic interventions in diseases

The Commander complex's three-dimensional arrangement and the extent of its interaction landscape has remained a mystery until now. The research team employed cryogenic electron microscopy to capture the structure, complemented by mass spectrometry to analyze complex interactions within cells.

The analysis revealed mutations within the complex associated with developmental disorders. This research opens avenues for potential therapeutic interventions in diseases, such as the Ritscher-Schinzel syndrome, Alzheimer’s Disease, and viral infections like COVID-19, linked to the Commander complex.

"With the combination of our techniques, we can truly start building a large-scale mechanistic picture of how these fundamental cellular machineries function in our bodies and what happens when things go wrong in them”, Dr. Esa-Pekka Kumpula, one of the study's lead authors, emphasizes.

“We saw first-hand that despite the advent of excellent predictive models, experimental evidence is still critical for determining the correct, biologically relevant structure”, he continues.
 

The study was financially supported by the Research Council of Finland, Biocenter Finland, University of Helsinki, The Sigrid Juselius Foundation, The Emil Aaltonen Foundation, Instrumentarium Science Foundation, and the Cancer Foundation Finland.
 

Fact: The Commander complex orchestrates endosomal sorting

• The Commander complex is an assembly of 16 protein components orchestrating a crucial process called endosomal sorting.
• This process manages internalized receptors, transported within the cell on small lipid vesicles, deciding whether they are destined for degradation or recycling back to the cell membrane.
• The Commander complex's role in maintaining surface receptors is pivotal, and disruptions in its function can lead to a spectrum of diseases, including neurodevelopmental disorders, neurodegenerative diseases, cancer, and immune disorders.