PMC:2726924 / 15463-17687
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2726924","sourcedb":"PMC","sourceid":"2726924","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2726924","text":"The most remarkable feature of the amyloid state of β2m is the dimer-of-dimers building block assembled into protofilaments that associate asymmetrically into the crescent-shaped units (Fig. 6). The resulting fibril architecture is discontinuous and very open, consistent with hydrogen-exchange protection factors of ∼ 103–104 along the sequence of β2m amyloid fibrils47 and the observation of pressure-induced fibril compaction.48 The elaborate fibril assembly reveals at least three non-equivalent subunit contacts. In the plane of each crescent, one protofilament makes the back-to-back connection to the equivalent protofilament in the opposite crescent, the central one links to a neighbour on either side, and the peripheral protofilament makes only one neighbour contact (Fig. 6b). Therefore, the β2m amyloid state does not simply arise from the same conformation in all subunits and, in marked contrast to the generic idea of amyloid as a continuous β-ribbon, the β2m protofilaments resemble a string of beads rather than a continuous β-sheet assembly. Importantly, the EM maps reveal that the globular repeat forms an integral part of the fibril structure and is not a folded “passenger” domain located externally to the fibril backbone, as seen, for example, in fibrils of Sup35 and Ure2p.49,50 This result is consistent with limited proteolysis experiments that revealed participation of ∼ 90 of the 99 residues in the fibril core and with hydrogen exchange measurements showing also an extensive protected core, with exchange kinetics suggestive of multiple environments for individual residues within the fibril structure.47,51 Such a complex architecture is also consistent with the observed importance of numerous stretches of the β2m polypeptide sequence in fibril formation.41,52,53 We note that a globular repeat is not unique to the β2m fibrils presented here, but has been suggested in earlier lower-resolution studies of fibrils formed from SH3 domains and the mammalian prion protein.34,36 Future models of amyloid will need to take into account the multiple intermolecular associations within a single homopolymer, most notably for fibrils formed from protein subunits, rather than peptide precursors.","tracks":[{"project":"2_test","denotations":[{"id":"19345691-15081813-62520790","span":{"begin":368,"end":370},"obj":"15081813"},{"id":"19345691-16122756-62520791","span":{"begin":429,"end":431},"obj":"16122756"},{"id":"19345691-9182769-62520792","span":{"begin":1302,"end":1304},"obj":"9182769"},{"id":"19345691-15143215-62520792","span":{"begin":1302,"end":1304},"obj":"15143215"},{"id":"19345691-15081813-62520793","span":{"begin":1638,"end":1640},"obj":"15081813"},{"id":"19345691-16636995-62520793","span":{"begin":1638,"end":1640},"obj":"16636995"},{"id":"19345691-16537488-62520794","span":{"begin":1797,"end":1799},"obj":"16537488"},{"id":"19345691-12705891-62520794","span":{"begin":1797,"end":1799},"obj":"12705891"},{"id":"19345691-12488093-62520794","span":{"begin":1797,"end":1799},"obj":"12488093"},{"id":"19345691-10022824-62520795","span":{"begin":2009,"end":2011},"obj":"10022824"},{"id":"19345691-16473369-62520795","span":{"begin":2009,"end":2011},"obj":"16473369"}],"attributes":[{"subj":"19345691-15081813-62520790","pred":"source","obj":"2_test"},{"subj":"19345691-16122756-62520791","pred":"source","obj":"2_test"},{"subj":"19345691-9182769-62520792","pred":"source","obj":"2_test"},{"subj":"19345691-15143215-62520792","pred":"source","obj":"2_test"},{"subj":"19345691-15081813-62520793","pred":"source","obj":"2_test"},{"subj":"19345691-16636995-62520793","pred":"source","obj":"2_test"},{"subj":"19345691-16537488-62520794","pred":"source","obj":"2_test"},{"subj":"19345691-12705891-62520794","pred":"source","obj":"2_test"},{"subj":"19345691-12488093-62520794","pred":"source","obj":"2_test"},{"subj":"19345691-10022824-62520795","pred":"source","obj":"2_test"},{"subj":"19345691-16473369-62520795","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ecbb93","default":true}]}]}}