{"id":{"repo_id":"soton","oai_identifier":"oai:eprints.soton.ac.uk:167063"},"canonical_url":"https://search.dev.ndltd.org/etd/soton/oai:eprints.soton.ac.uk:167063","repository":{"repo_id":"soton","name":"University of Southampton","base_url":"https://eprints.soton.ac.uk/cgi/oai2"},"display":{"title":"Protein mis-folding and human disease","abstract":"Serum Amyloid P Component (SAP), a putative molecular chaperone, is a homopentameric
plasma protein of 25kDa subunits. It binds to the amyloid fibrils of
misfolded proteins, which cause amyloidosis in humans. SAP not only stabilizes
amyloid fibrils but also protects them from proteolytic and cell mediated
degradation. SAP has been co-crystallized with three different aminoalkyl
phosphonates that bind at the amyloid recognition site of SAP, and the X-ray
crystal structures were determined at atomic resolution.
A secondary aim of this work was to understand the enhanced amyloidogenic
potential of L55P and V30M transthyretin (TTR) protein. TTR misfolding has been
implicated in number of human diseases such as senile systemic amyloidosis,
familial amyloid polyneuropathy and familial amyloid cardiopathy. TTR protein is a
thyroxine binding protein (14kDa) existing as a tetramer in vivo. L55P and V30M
mutant TTR are the most aggressive and most common mutants, respectively, in
causing FAP. L55P and V30M mutant TTR protein were expressed in E.coli and
purified using anion-exchange chromatography and gel filtration. L55P and V30M
TTR were co-crystallised with MDS84, a compound that has been demonstrated to
stabilize the tetramer in vitro. The X-ray structures of L55P and V30M, TTR mutant
proteins have been determined at 1.5Å and 2.1Å resolution.
In addition, research was carried out on the bacterial protein Burkholderia invasion
protein D (BipD). BipD (33kDa) belongs to type III secretion system of Burkholderia
pseudomallei. It creates a pore in the host cell membrane to help the B.
pseudomallei invasion. This bacterial infection causes melioidosis disease in
humans. To determine the ligand recognition site of BipD, its high-resolution crystal
structure has been determined at 1.5Å. This high resolution BipD structure is more
complete than its previously solved structures and is in the new space group C2.
The BipD structure presented in this research may help to design potential
chemical inhibitors of BipD to prevent bacterial invasion into human body.
The molecular chaperones play an important role in the protein refolding and
assembly. ATJ11 is of 14kDa protein belongs to DnaJ co-chaperone family. The
protein has been expressed in E.coli and purified by affinity and cation exchange
chromatography. The biophysical study of ATJ11 (CD spectrum) has been
conducted showing its predominant ?-helical structure and attempts were made to
crystallise it but no protein crystals have been obtained.
","abstract_html":"Serum Amyloid P Component (SAP), a putative molecular chaperone, is a homopentameric<br/>plasma protein of 25kDa subunits. It binds to the amyloid fibrils of<br/>misfolded proteins, which cause amyloidosis in humans. SAP not only stabilizes<br/>amyloid fibrils but also protects them from proteolytic and cell mediated<br/>degradation. SAP has been co-crystallized with three different aminoalkyl<br/>phosphonates that bind at the amyloid recognition site of SAP, and the X-ray<br/>crystal structures were determined at atomic resolution.<br/><br/>A secondary aim of this work was to understand the enhanced amyloidogenic<br/>potential of L55P and V30M transthyretin (TTR) protein. TTR misfolding has been<br/>implicated in number of human diseases such as senile systemic amyloidosis,<br/>familial amyloid polyneuropathy and familial amyloid cardiopathy. TTR protein is a<br/>thyroxine binding protein (14kDa) existing as a tetramer in vivo. L55P and V30M<br/>mutant TTR are the most aggressive and most common mutants, respectively, in<br/>causing FAP. L55P and V30M mutant TTR protein were expressed in E.coli and<br/>purified using anion-exchange chromatography and gel filtration. L55P and V30M<br/>TTR were co-crystallised with MDS84, a compound that has been demonstrated to<br/>stabilize the tetramer in vitro. The X-ray structures of L55P and V30M, TTR mutant<br/>proteins have been determined at 1.5Å and 2.1Å resolution.<br/><br/>In addition, research was carried out on the bacterial protein Burkholderia invasion<br/>protein D (BipD). BipD (33kDa) belongs to type III secretion system of Burkholderia<br/>pseudomallei. It creates a pore in the host cell membrane to help the B.<br/>pseudomallei invasion. This bacterial infection causes melioidosis disease in<br/>humans. To determine the ligand recognition site of BipD, its high-resolution crystal<br/>structure has been determined at 1.5Å. This high resolution BipD structure is more<br/>complete than its previously solved structures and is in the new space group C2.<br/>The BipD structure presented in this research may help to design potential<br/>chemical inhibitors of BipD to prevent bacterial invasion into human body.<br/><br/>The molecular chaperones play an important role in the protein refolding and<br/>assembly. ATJ11 is of 14kDa protein belongs to DnaJ co-chaperone family. The<br/>protein has been expressed in E.coli and purified by affinity and cation exchange<br/>chromatography. The biophysical study of ATJ11 (CD spectrum) has been<br/>conducted showing its predominant ?-helical structure and attempts were made to<br/>crystallise it but no protein crystals have been obtained.<br/>","abstract_has_math":false,"creators":["Pal, Mohinder"],"institution":"University of Southampton","degree_name":"Ph.D.","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Wood, Steve P.","Coker, A.R."],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07","date_published":"2010-07","updated_at":"2026-07-24T04:36:17Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Wood, Steve P.","Coker, A.R."]},{"key":"dc:creator","label":"Author","values":["Pal, Mohinder"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07"]},{"key":"dc:date.issued","label":"Date","values":["2010-07"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Biological Sciences (pre 2011 reorg)","School of Biological Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Southampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://eprints.soton.ac.uk/167063/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Ph.D."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://eprints.soton.ac.uk/167063/1/Mohinder_Pal.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Serum Amyloid P Component (SAP), a putative molecular chaperone, is a homopentameric
plasma protein of 25kDa subunits. It binds to the amyloid fibrils of
misfolded proteins, which cause amyloidosis in humans. SAP not only stabilizes
amyloid fibrils but also protects them from proteolytic and cell mediated
degradation. SAP has been co-crystallized with three different aminoalkyl
phosphonates that bind at the amyloid recognition site of SAP, and the X-ray
crystal structures were determined at atomic resolution.
A secondary aim of this work was to understand the enhanced amyloidogenic
potential of L55P and V30M transthyretin (TTR) protein. TTR misfolding has been
implicated in number of human diseases such as senile systemic amyloidosis,
familial amyloid polyneuropathy and familial amyloid cardiopathy. TTR protein is a
thyroxine binding protein (14kDa) existing as a tetramer in vivo. L55P and V30M
mutant TTR are the most aggressive and most common mutants, respectively, in
causing FAP. L55P and V30M mutant TTR protein were expressed in E.coli and
purified using anion-exchange chromatography and gel filtration. L55P and V30M
TTR were co-crystallised with MDS84, a compound that has been demonstrated to
stabilize the tetramer in vitro. The X-ray structures of L55P and V30M, TTR mutant
proteins have been determined at 1.5Å and 2.1Å resolution.
In addition, research was carried out on the bacterial protein Burkholderia invasion
protein D (BipD). BipD (33kDa) belongs to type III secretion system of Burkholderia
pseudomallei. It creates a pore in the host cell membrane to help the B.
pseudomallei invasion. This bacterial infection causes melioidosis disease in
humans. To determine the ligand recognition site of BipD, its high-resolution crystal
structure has been determined at 1.5Å. This high resolution BipD structure is more
complete than its previously solved structures and is in the new space group C2.
The BipD structure presented in this research may help to design potential
chemical inhibitors of BipD to prevent bacterial invasion into human body.
The molecular chaperones play an important role in the protein refolding and
assembly. ATJ11 is of 14kDa protein belongs to DnaJ co-chaperone family. The
protein has been expressed in E.coli and purified by affinity and cation exchange
chromatography. The biophysical study of ATJ11 (CD spectrum) has been
conducted showing its predominant ?-helical structure and attempts were made to
crystallise it but no protein crystals have been obtained.
"]},{"key":"dc:format","label":"Dc Format","values":["text"]},{"key":"dc:title","label":"Title","values":["Protein mis-folding and human disease"]}]}],"canonical_facts":{"dc:contributor.advisor":["Wood, Steve P.","Coker, A.R."],"dc:creator":["Pal, Mohinder"],"dc:date":["2010-07"],"dc:date.issued":["2010-07"],"dc:description.abstract":["Serum Amyloid P Component (SAP), a putative molecular chaperone, is a homopentameric
plasma protein of 25kDa subunits. It binds to the amyloid fibrils of
misfolded proteins, which cause amyloidosis in humans. SAP not only stabilizes
amyloid fibrils but also protects them from proteolytic and cell mediated
degradation. SAP has been co-crystallized with three different aminoalkyl
phosphonates that bind at the amyloid recognition site of SAP, and the X-ray
crystal structures were determined at atomic resolution.
A secondary aim of this work was to understand the enhanced amyloidogenic
potential of L55P and V30M transthyretin (TTR) protein. TTR misfolding has been
implicated in number of human diseases such as senile systemic amyloidosis,
familial amyloid polyneuropathy and familial amyloid cardiopathy. TTR protein is a
thyroxine binding protein (14kDa) existing as a tetramer in vivo. L55P and V30M
mutant TTR are the most aggressive and most common mutants, respectively, in
causing FAP. L55P and V30M mutant TTR protein were expressed in E.coli and
purified using anion-exchange chromatography and gel filtration. L55P and V30M
TTR were co-crystallised with MDS84, a compound that has been demonstrated to
stabilize the tetramer in vitro. The X-ray structures of L55P and V30M, TTR mutant
proteins have been determined at 1.5Å and 2.1Å resolution.
In addition, research was carried out on the bacterial protein Burkholderia invasion
protein D (BipD). BipD (33kDa) belongs to type III secretion system of Burkholderia
pseudomallei. It creates a pore in the host cell membrane to help the B.
pseudomallei invasion. This bacterial infection causes melioidosis disease in
humans. To determine the ligand recognition site of BipD, its high-resolution crystal
structure has been determined at 1.5Å. This high resolution BipD structure is more
complete than its previously solved structures and is in the new space group C2.
The BipD structure presented in this research may help to design potential
chemical inhibitors of BipD to prevent bacterial invasion into human body.
The molecular chaperones play an important role in the protein refolding and
assembly. ATJ11 is of 14kDa protein belongs to DnaJ co-chaperone family. The
protein has been expressed in E.coli and purified by affinity and cation exchange
chromatography. The biophysical study of ATJ11 (CD spectrum) has been
conducted showing its predominant ?-helical structure and attempts were made to
crystallise it but no protein crystals have been obtained.
"],"dc:format":["text"],"dc:identifier.uri":["https://eprints.soton.ac.uk/167063/1/Mohinder_Pal.pdf"],"dc:publisher.department":["Biological Sciences (pre 2011 reorg)","School of Biological Sciences"],"dc:publisher.institution":["University of Southampton"],"dc:relation.isreferencedby":["https://eprints.soton.ac.uk/167063/"],"dc:title":["Protein mis-folding and human disease"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["Ph.D."]},"updated_at":"2026-07-24T04:36:17Z"}