X-ray crystal structure of MENT: evidence for functional loop-sheet polymers in chromatin condensation.
Most serpins are associated with protease inhibition, and their ability to form loop-sheet polymers is linked to conformational disease and the human serpinopathies. Here we describe the structural and functional dissection of how a unique serpin, the non-histone architectural protein, MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein), participates in DNA and chromatin condensation. Our data suggest that MENT contains at least two distinct DNA-binding sites, consistent with its simultaneous binding to the two closely juxtaposed linker DNA segments on a nucleosome. Remarkably, our studies suggest that the reactive centre loop, a region of the MENT molecule essential for chromatin bridging in vivo and in vitro, is able to mediate formation of a loop-sheet oligomer. These data provide mechanistic insight into chromatin compaction by a non-histone architectural protein and suggest how the structural plasticity of serpins has adapted to mediate physiological, rather than pathogenic, loop-sheet linkages.
McGowan
Sheena
S
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Buckle
Ashley M
AM
Irving
James A
JA
Ong
Poh Chee
PC
Bashtannyk-Puhalovich
Tanya A
TA
Kan
Wan-Ting
WT
Henderson
Kate N
KN
Bulynko
Yaroslava A
YA
Popova
Evgenya Y
EY
Smith
A Ian
AI
Bottomley
Stephen P
SP
Rossjohn
Jamie
J
Grigoryev
Sergei A
SA
Pike
Robert N
RN
Whisstock
James C
JC
D000818:Animals; D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry; D002843:Chromatin / Q000378:metabolism*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009707:Nucleosomes / Q000378:metabolism; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; D009707:Nucleosomes; D015843:Serpins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L