Molecular basis for governing the morphology of type-I collagen fibrils by Osteomodulin

Small leucine-rich repeat proteoglycan (SLRP) proteins have an important role in the organization of the extracellular matrix, especially in the formation of collagen fibrils. However, the mechanism governing the shape of collagen fibrils is poorly understood. Here, we report that the protein Osteomodulin (OMD) of the SLRP family is a monomeric protein in solution that interacts with type-I collagen. This interaction is dominated by weak electrostatic forces employing negatively charged residues of OMD, in particular Glu284 and Glu303, and controlled by entropic factors. The protein OMD establishes a fast-binding equilibrium with collagen, where OMD may engage not only with individual collagen molecules, but also with the growing fibrils. This weak electrostatic interaction is carefully balanced so it modulates the shape of the fibrils without compromising their viability

The non-equivariant coherent-constructible correspondence and a conjecture of King

The coherent-constructible (CC) correspondence is a relationship between coherent sheaves on a toric variety X and constructible sheaves on a real torus $$mathbb {T}$$T. This was discovered by Bondal and established in the equivariant setting by Fang, Liu, Treumann, and Zaslow. In this paper, we explore various aspects of the non-equivariant CC correspondence. Also, we use the non-equivariant CC correspondence to prove the existence of tilting complexes in the derived categories of toric orbifolds satisfying certain combinatorial conditions. This has applications to a conjecture of King

Molecular basis for governing the morphology of type-I collagen fibrils by Osteomodulin

Takumi Tashima and colleagues provide structural insights into how collagen fibrils are shaped by Osteomodulin. Osteomodulin keeps a fast-binding equilibrium with the collagen fibrils to slow down its growth, promoting the formation of uniform, intact collagen fibrils

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy

Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI 1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy