A RIKEN-led team of molecular biologists has determined the specific bonding leading to the formation of a protein complex involved in distributing pigment throughout the skin. Disruption of this membrane transport complex leads to the rare, lethal Griscelli syndrome for which there is no effective treatment.
Patients show symptoms of albinism, suffer immunodeficiency, and typically die in early childhood. The work may stimulate the development of therapeutic drugs for the condition.
Members of the Rab protein family—of which there are more than 60 in humans—are thought to be essential to membrane trafficking, an important form of communication and distribution within cells. Rab proteins are typically bound to membranes either in an inactive guanine diphosphate form or an active triphosphate form which works through specific effector molecules to promote membrane trafficking.
The pigment melanin, which protects against radiation damage, is made and distributed within vesicles called melanosomes in skin color cells known as melanocytes. Rab27, which comes in two forms A and B, binds into a complex with the effector protein Slac2-a and myosin Va to transfer melanosomes onto actin filaments. The complex then transports the melanosomes along the filaments to where Rab27 uses another effector molecule to anchor them to the outer membrane of the cell.
Researchers from the RIKEN Systems and Structural Biology Center in Yokohama together with colleagues from Tohoku University were able to crystallize the Rab27B/Slac2-a complex and solve its structure using x-ray diffraction. As active Rab27 proteins are notoriously difficult to crystallize, this was the first mammalian complex where the binding of such a protein with its effector molecule could be thoroughly investigated. The results were published recently in the journal Structure1.
The researchers found three contact regions between Rab27B and Slac2-a, of which only one was involved in specific recognition. Mutations affecting any of the several specific intermolecular hydrogen bonds in this region were fundamentally disruptive, and some of them led to Griscelli’s syndrome. The group was able to verify the structure by taking another Rab protein, Rab3A, and engineering it to bind Slac2-a. The Rab3A amino acid sequence had to be altered by only four amino acid residues in the critical binding area to form the complex with Slac2-a.
“We are hoping that pharmaceutical companies will be able to use our structure as a basis for drugs which can be used to treat conditions like Griscelli’s syndrome,” says first author Mutsuko Kukimoto-Niino.
1. Kukimoto-Niino, M., Sakamoto, A., Kanno, E., Hanawa-Suetsugu, K., Terada, T., Shirouzu, M., Fukuda, M. & Yokoyama, S. Structural basis for the exclusive specificity of Slac2-a/melanophilin for the Rab27 GTPases. Structure 16, 1478–1490 (2008).
The corresponding author for this highlight is based at the RIKEN Systems and Structural Biology Research Center
Saeko Okada | ResearchSEA
Millions through license revenues
27.04.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
New High-Performance Center Translational Medical Engineering
26.04.2017 | Fraunhofer ITEM
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences