The Stuctural Studies Of Oncogenic MEF2D-fusion In Leukemia And BAM Machinery In Infectious Diseases

At present,diseases threatening human health mainly include malignant tumors,cardiovascular and cerebrovascular diseases,infectious diseases and so on.This paper is focused on leukemia and Gram-negative bacteria related infectious diseases for the purpose of improving people’s quality of life.B progenitor acute lymphoblastic leukemia(B-ALL)is characterized by recurrent gross chromosomal alterations.Recently,several MEF2 D fusion partners were identified: BCL9,HNRNPUL1,DAZAP1,CSF1 R and SS18 among a small number of B-ALL patients.Compared with other subtypes,MEF2D-related leukemia shows poorer prognosis.For these newly discovered fusion genes,people still do not know much about the pathogenesis and mechanism of leukemia,so the exploration and research of its mechanism is a further expansion of the leukemia field,and also provides a theory for the treatment of B-ALL in clinic.Through the study of protein molecular level,we obtained the crystal structure of the complex of MEF2 D and DNA,and the diffraction resolution reached 3 angstroms,which can provide us with clear spatial structure information.Through structural information,we designed R3 A,K4A,K5 A.The R15 A,K23A,and K31 A mutations were verified by BLI and Luciferase experiments.These binding sites that interact with DNA can serve as potential targets for future leukemia treatment.Almost all the outer membrane proteins(OMPs)in gram-negative bacteria fold into a ?-barrel fold via the poly-POTRA motif and ?-barrel assembly machinery(BAM).However,the mechanism of the OMP-POTRA interaction/recruitment remains poorly understood.Until now,we have solved the crystal structure of H.influenzae poly-POTRAs.The H.influenzae poly-POTRAs structures revealed remarkable protein flexibility between different POTRA subunits.Furthermore,the phylogenetic analysis and structure-based sequence alignment of bacterial poly-POTRAs revealed an unexpected finding: more the POTRA subunits and protein flexibility,more lipo-associates are required.The restriction of POTRA-POTRA flexibility impaired the interactions of POTRA-lipoprotein,resulting in severe bacterial growth defect.Thus we can design drugs preventing OMP-POTRA interaction/recruitment to treat patients infected by gram-negative bacteria.