Ribitol-phosphate: chemical tools to probe the biology of a unique mammalian carbohydrate

Descripción del proyecto

El estudio de un glicano defectuoso podría ayudar a tratar enfermedades musculares devastadoras

Las proteínas son los caballos de batalla de las células, la piedra angular de las moléculas para receptores, inmunoglobulinas y hormonas, entre otras. Durante o después de la traducción, la mayoría de las proteínas se «decoran» con hidratos de carbono durante la glicosilación, un proceso altamente regulado que afecta a su estructura en tridimensional, su función y su estabilidad. Cuando este proceso sale mal, las proteínas defectuosas pueden desempeñar un papel en los procesos de enfermedad. El proyecto RibiTool, financiado con fondos europeos, investiga un glicano único de la superficie celular cuyo ensamblaje incorrecto da lugar a los tipos de distrofia muscular congénita (enfermedad muscular caracterizada por la degeneración progresiva de los músculos) denominados alfa-distroglicanopatía. Las herramientas desarrolladas en el marco del proyecto facilitarán el estudio del ensamblaje, la estructura y la función del glicano, lo cual podría abrir la puerta a terapias para estas enfermedades devastadoras.

Objetivo

Cell-surface proteins are decorated with a variety of different carbohydrate structures that play central roles in mammalian biology. The complex nature of glycan structures and the pathways by which they are assembled make it a challenging task to decipher their exact function in cells, knowledge that is essential if we are to understand how malfunctioning leads to disease. This proposal aims to deliver innovative approaches to probe a distinct pathway of glycosylation essential to mammalian biology and to use these strategies to provide novel insights into the mechanisms underlying normal cellular functioning and disease pathology. The work programme is built around a specific type of O-linked cell-surface glycan that carries two critical ribitol-phosphate (RboP) residues, unique carbohydrates that so far have not been identified in other mammalian glycoconjugates. Failure to correctly assemble this glycan causes a range of congenital muscular dystrophies known as α-dystroglycanopathies. Despite its importance in disease pathology, many aspects of RboP utilisation and functioning in mammalian cells are poorly understood. The proposed programme offers a powerful and original approach to address these key issues in cell biology by creating a set of novel chemical tools. These tools will enable the probing and manipulation of both RboP-carrying glycoconjugates as well as the enzymes responsible for installing RboP onto the glycans in a cellular context. Integration of these tools with fundamental 3-D structural information and studies in cellular models of α-dystroglycanopathy will offer the unprecedented opportunity to directly link genetic defects to molecular and cellular aspects of enzyme function and through to observed changes in glycosylation status. These pioneering strategies will impact our fundamental understanding of key processes in mammalian cells and will also enable the exploitation of this unique pathway for the design of therapeutic strategies.