Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein
Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis,...
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| Veröffentlicht in: | The Journal of biological chemistry 2008-06, Vol.283 (23), p.15853-15860 |
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| container_title | The Journal of biological chemistry |
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| creator | Baden, Elizabeth M. Owen, Barbara A.L. Peterson, Francis C. Volkman, Brian F. Ramirez-Alvarado, Marina Thompson, James R. |
| description | Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis, which results from deposition of light chains produced by clonal plasma cells. We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the κI O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90° from the κI O18/O8 dimer interface. The three non-conservative mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than κI O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins. |
| doi_str_mv | 10.1074/jbc.M705347200 |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis, which results from deposition of light chains produced by clonal plasma cells. We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the κI O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90° from the κI O18/O8 dimer interface. The three non-conservative mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than κI O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M705347200</identifier><identifier>PMID: 18400753</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Amyloid - chemistry ; Amyloid - genetics ; Amyloid - metabolism ; Amyloidosis - drug therapy ; Amyloidosis - genetics ; Amyloidosis - metabolism ; BASIC BIOLOGICAL SCIENCES ; DAMAGE ; DEPOSITION ; DESIGN ; Dimerization ; DIMERS ; DISEASES ; Drug Design ; DRUGS ; Humans ; Immunoglobulin kappa-Chains - chemistry ; Immunoglobulin kappa-Chains - genetics ; Immunoglobulin kappa-Chains - metabolism ; IMMUNOGLOBULINS ; IN VITRO ; INTERFACES ; MONOMERS ; Mutation ; MUTATIONS ; ORGANS ; PLASMA CELLS ; Plasma Cells - metabolism ; Protein Structure and Folding ; Protein Structure, Quaternary ; PROTEINS ; STABILITY</subject><ispartof>The Journal of biological chemistry, 2008-06, Vol.283 (23), p.15853-15860</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>Copyright © 2008, The American Society for Biochemistry and Molecular Biology, Inc. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c614t-178c74ec2f8c6ddfdf0031d16236fb876892e61f1e51acd1f82740762a950d453</citedby><cites>FETCH-LOGICAL-c614t-178c74ec2f8c6ddfdf0031d16236fb876892e61f1e51acd1f82740762a950d453</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2414275/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2414275/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18400753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1006666$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Baden, Elizabeth M.</creatorcontrib><creatorcontrib>Owen, Barbara A.L.</creatorcontrib><creatorcontrib>Peterson, Francis C.</creatorcontrib><creatorcontrib>Volkman, Brian F.</creatorcontrib><creatorcontrib>Ramirez-Alvarado, Marina</creatorcontrib><creatorcontrib>Thompson, James R.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis, which results from deposition of light chains produced by clonal plasma cells. We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the κI O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90° from the κI O18/O8 dimer interface. The three non-conservative mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than κI O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Amyloid - chemistry</subject><subject>Amyloid - genetics</subject><subject>Amyloid - metabolism</subject><subject>Amyloidosis - drug therapy</subject><subject>Amyloidosis - genetics</subject><subject>Amyloidosis - metabolism</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>DAMAGE</subject><subject>DEPOSITION</subject><subject>DESIGN</subject><subject>Dimerization</subject><subject>DIMERS</subject><subject>DISEASES</subject><subject>Drug Design</subject><subject>DRUGS</subject><subject>Humans</subject><subject>Immunoglobulin kappa-Chains - chemistry</subject><subject>Immunoglobulin kappa-Chains - genetics</subject><subject>Immunoglobulin kappa-Chains - metabolism</subject><subject>IMMUNOGLOBULINS</subject><subject>IN VITRO</subject><subject>INTERFACES</subject><subject>MONOMERS</subject><subject>Mutation</subject><subject>MUTATIONS</subject><subject>ORGANS</subject><subject>PLASMA CELLS</subject><subject>Plasma Cells - metabolism</subject><subject>Protein Structure and Folding</subject><subject>Protein Structure, Quaternary</subject><subject>PROTEINS</subject><subject>STABILITY</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFvEzEQhVcIREPhyhFWCHFLmbG9a-eCFLVQKhWBVCpxsxx7NnG1axd7U5R_j8NGFA6IuVjWfH7zPK-qniOcIEjx9mZlTz5JaLiQDOBBNUNQfM4b_PawmgEwnC9Yo46qJznfQCmxwMfVESoBIBs-q86X_UiJXH3mB0r1RSi3zliqz8gmMplyfTWale_9uKt9qE2ol8Ouj97FNQVv6y8pjuTD0-pRZ_pMzw7ncXX94f3X04_zy8_nF6fLy7ltUYxzlMpKQZZ1yrbOda4D4OiwZbztVkq2asGoxQ6pQWMddopJAbJlZtGAEw0_rt5Nurfb1UDOUhiT6fVt8oNJOx2N1393gt_odbzTTKBgci_wahKIefQ6Wz-S3dgYAtlRI0BbqkBvDlNS_L6lPOrBZ0t9bwLFbdayGBaK8f-CDKSSUu3Bkwm0KeacqPttGUHvk9QlSX2fZHnw4s-P3uOH6ArwegI2fr354RPplY92Q4NmimvGNTbqF_ZywjoTtVknn_X1FQPkAIsyhmEh1ERQye3OU9pvhYIlV0TLUlz0_zL5EwQMwMM</recordid><startdate>20080606</startdate><enddate>20080606</enddate><creator>Baden, Elizabeth M.</creator><creator>Owen, Barbara A.L.</creator><creator>Peterson, Francis C.</creator><creator>Volkman, Brian F.</creator><creator>Ramirez-Alvarado, Marina</creator><creator>Thompson, James R.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20080606</creationdate><title>Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein</title><author>Baden, Elizabeth M. ; Owen, Barbara A.L. ; Peterson, Francis C. ; Volkman, Brian F. ; Ramirez-Alvarado, Marina ; Thompson, James R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c614t-178c74ec2f8c6ddfdf0031d16236fb876892e61f1e51acd1f82740762a950d453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Amyloid - chemistry</topic><topic>Amyloid - genetics</topic><topic>Amyloid - metabolism</topic><topic>Amyloidosis - drug therapy</topic><topic>Amyloidosis - genetics</topic><topic>Amyloidosis - metabolism</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>DAMAGE</topic><topic>DEPOSITION</topic><topic>DESIGN</topic><topic>Dimerization</topic><topic>DIMERS</topic><topic>DISEASES</topic><topic>Drug Design</topic><topic>DRUGS</topic><topic>Humans</topic><topic>Immunoglobulin kappa-Chains - chemistry</topic><topic>Immunoglobulin kappa-Chains - genetics</topic><topic>Immunoglobulin kappa-Chains - metabolism</topic><topic>IMMUNOGLOBULINS</topic><topic>IN VITRO</topic><topic>INTERFACES</topic><topic>MONOMERS</topic><topic>Mutation</topic><topic>MUTATIONS</topic><topic>ORGANS</topic><topic>PLASMA CELLS</topic><topic>Plasma Cells - metabolism</topic><topic>Protein Structure and Folding</topic><topic>Protein Structure, Quaternary</topic><topic>PROTEINS</topic><topic>STABILITY</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baden, Elizabeth M.</creatorcontrib><creatorcontrib>Owen, Barbara A.L.</creatorcontrib><creatorcontrib>Peterson, Francis C.</creatorcontrib><creatorcontrib>Volkman, Brian F.</creatorcontrib><creatorcontrib>Ramirez-Alvarado, Marina</creatorcontrib><creatorcontrib>Thompson, James R.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). 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We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the κI O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90° from the κI O18/O8 dimer interface. The three non-conservative mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than κI O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18400753</pmid><doi>10.1074/jbc.M705347200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 60 APPLIED LIFE SCIENCES Amyloid - chemistry Amyloid - genetics Amyloid - metabolism Amyloidosis - drug therapy Amyloidosis - genetics Amyloidosis - metabolism BASIC BIOLOGICAL SCIENCES DAMAGE DEPOSITION DESIGN Dimerization DIMERS DISEASES Drug Design DRUGS Humans Immunoglobulin kappa-Chains - chemistry Immunoglobulin kappa-Chains - genetics Immunoglobulin kappa-Chains - metabolism IMMUNOGLOBULINS IN VITRO INTERFACES MONOMERS Mutation MUTATIONS ORGANS PLASMA CELLS Plasma Cells - metabolism Protein Structure and Folding Protein Structure, Quaternary PROTEINS STABILITY |
| title | Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein |
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