Inside every cell, a sophisticated logistics network keeps proteins, membranes and other components moving to the right place at the right time. Two closely related protein assemblies, known as BLOC-1 (Biogenesis of Lysosome-Related Organelles Complex-1) and BORC (BLOC-1 related complex), are key in coordinating this intracellular traffic. BLOC-1 coordinates cargo delivery to specialised compartments such as lysosomes, the cell’s recycling centres, and pigment granules. BORC, by contrast, controls where lysosomes are positioned within the cell, linking them to molecular motors that move along the cytoskeleton.
The hidden complexity of cell logistics
For years, scientists assumed that BLOC-1 and BORC were essentially single, uniform machines, each built from a set of parts in the same fixed proportions. In a new study published now in the journal PNAS, researchers in the groups of David Haselbach and Tim Clausen at the Research Institute of Molecular Pathology (IMP) and their collaborators around former IMP group leader Lukas Huber (now at the Medical University of Innsbruck) overturn this simple picture. Instead, these systems come in multiple versions, with different combinations and numbers of components coming together to form distinct complexes: Some proteins are shared across these assemblies, while others are present only in certain variants.
What made this hidden diversity visible was the team’s ability to see the complexes directly. Based on earlier biochemical data, they expected to visualize a large structure containing all known BLOC-1 or BORC subunits assembled together. Instead, cryo-EM data consistently revealed fewer a-helices in the structure than the “one big complex” model predicted.
“This mismatch led to a crucial realisation: Not all components are present at the same time,” Haselbach explains. Rather, BLOC-1 and BORC share a common core that can be combined with different additional subunits to form multiple, specialised assemblies. Some of these assemblies correspond to the “classic” BLOC-1 or BORC complexes, while others are hybrids that blend elements of both.
Why the system never behaved as expected
“It was like building a flat-pack bookcase and finding lots of parts left over after assembly,” Haselbach says. “What we’ve shown is that those ‘extra’ pieces aren’t mistakes—they’re optional modules that can be combined with a shared frame to build different kinds of furniture.”
This insight reframes years of confusing experimental results: When researchers removed individual subunits and saw only subtle or inconsistent effects, it was not because those proteins were unimportant. Instead, each component turned out to matter only for certain members of this complex family, and its loss was masked by the continued presence of other assemblies. This modular character allows the cell to assemble the complex required to meet different transport needs.
The implications extend beyond cell biology. Defects in the components of BLOC-1 and BORC have been linked to neurodevelopmental disorders, pigmentation defects, and cancer. “If these complexes exist in multiple forms—including hybrid BORC–BLOC-1 assemblies—then understanding exactly which version is disrupted in a given disease becomes critical”, Haselbach adds. Future therapies will depend on this level of precision: targeting the wrong complex could be ineffective or even harmful, while hitting the relevant assembly could open the door to more specific, tailored interventions.
Original publication
Mariana E.G. de Araujo, Sascha Amann, Taras Stasyk, Alexander Schleiffer, Eva Rauch, Paula Flümann, Isabel Singer, Leopold Kremser, Vojtech Dostal, Thanida Laopanupong, Nikolaus Obojes, Moritz H. Wallnöfer, Flora S. Gradl, Robert Kurzbauer, Caroline Krebiehl, Samuel Kofler, Irina Grishkovskaya, Georg F. Vogel, Michael W. Hess, Bettina Sarg, Tim Clausen; David Haselbach and Lukas A. Huber (2026): "BORC assemblies integrate BLOC-1 subunits to diversify endosomal trafficking functions". PNAS (2026). DOI: 10.1073/pnas.2515691123