TY - JOUR
T1 - Modelling of thyroid peroxidase reveals insights into its enzyme function and autoantigenicity
AU - Le, Sarah N.
AU - Porebski, Benjamin T.
AU - McCoey, Julia
AU - Fodor, James
AU - Riley, Blake
AU - Godlewska, Marlena
AU - Góra, Monika
AU - Czarnocka, Barbara
AU - Paul Banga, J.
AU - Hoke, David E.
AU - Kass, Itamar
AU - Buckle, Ashley M.
N1 - Publisher Copyright:
© 2015 Le et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease-themost common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directedmainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined.We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-Terminus are consistent with a coiled-coil dimerization motif thatmost likely anchors the TPO dimer in the apicalmembrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of themyeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO-And CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, themodelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.
AB - Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease-themost common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directedmainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined.We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-Terminus are consistent with a coiled-coil dimerization motif thatmost likely anchors the TPO dimer in the apicalmembrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of themyeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO-And CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, themodelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.
UR - http://www.scopus.com/inward/record.url?scp=84961348485&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0142615
DO - 10.1371/journal.pone.0142615
M3 - Article
C2 - 26623656
AN - SCOPUS:84961348485
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e0142615
ER -