Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells

Andrew T Hutchinson, Ansha Malik, Mark B Berkahn, Mark James Agostino, Joyce To, Jessica L Tacchi, Steven P Djordjevic, Lynne Turnbull, Cynthia Beth Whitchurch, A B Edmundson, Darren R Jones, Robert L Raison, Paul Allen Ramsland

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Abstract

We have described the presence of cell-membrane-associated kFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-?FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for ? light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether ?FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of ?FLCs on the surface of myeloma cells. We found that cell-surface-associated ?FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that ?FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated ?FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen. ? 2013 Biochemical Society.
Original languageEnglish
Pages (from-to)479 - 489
Number of pages11
JournalBiochemical Journal
Volume454
Issue number3
DOIs
Publication statusPublished - 2013

Cite this

Hutchinson, Andrew T ; Malik, Ansha ; Berkahn, Mark B ; Agostino, Mark James ; To, Joyce ; Tacchi, Jessica L ; Djordjevic, Steven P ; Turnbull, Lynne ; Whitchurch, Cynthia Beth ; Edmundson, A B ; Jones, Darren R ; Raison, Robert L ; Ramsland, Paul Allen. / Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells. In: Biochemical Journal. 2013 ; Vol. 454, No. 3. pp. 479 - 489.
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title = "Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells",
abstract = "We have described the presence of cell-membrane-associated kFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-?FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for ? light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether ?FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of ?FLCs on the surface of myeloma cells. We found that cell-surface-associated ?FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that ?FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated ?FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen. ? 2013 Biochemical Society.",
author = "Hutchinson, {Andrew T} and Ansha Malik and Berkahn, {Mark B} and Agostino, {Mark James} and Joyce To and Tacchi, {Jessica L} and Djordjevic, {Steven P} and Lynne Turnbull and Whitchurch, {Cynthia Beth} and Edmundson, {A B} and Jones, {Darren R} and Raison, {Robert L} and Ramsland, {Paul Allen}",
year = "2013",
doi = "10.1042/BJ20130575",
language = "English",
volume = "454",
pages = "479 -- 489",
journal = "Biochemical Journal",
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publisher = "Portland Press",
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Hutchinson, AT, Malik, A, Berkahn, MB, Agostino, MJ, To, J, Tacchi, JL, Djordjevic, SP, Turnbull, L, Whitchurch, CB, Edmundson, AB, Jones, DR, Raison, RL & Ramsland, PA 2013, 'Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells', Biochemical Journal, vol. 454, no. 3, pp. 479 - 489. https://doi.org/10.1042/BJ20130575

Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells. / Hutchinson, Andrew T; Malik, Ansha; Berkahn, Mark B; Agostino, Mark James; To, Joyce; Tacchi, Jessica L; Djordjevic, Steven P; Turnbull, Lynne; Whitchurch, Cynthia Beth; Edmundson, A B; Jones, Darren R; Raison, Robert L; Ramsland, Paul Allen.

In: Biochemical Journal, Vol. 454, No. 3, 2013, p. 479 - 489.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Formation of assemblies on cell membranes by secreted proteins: molecular studies of free lambda light chain aggregates found on the surface of myeloma cells

AU - Hutchinson, Andrew T

AU - Malik, Ansha

AU - Berkahn, Mark B

AU - Agostino, Mark James

AU - To, Joyce

AU - Tacchi, Jessica L

AU - Djordjevic, Steven P

AU - Turnbull, Lynne

AU - Whitchurch, Cynthia Beth

AU - Edmundson, A B

AU - Jones, Darren R

AU - Raison, Robert L

AU - Ramsland, Paul Allen

PY - 2013

Y1 - 2013

N2 - We have described the presence of cell-membrane-associated kFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-?FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for ? light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether ?FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of ?FLCs on the surface of myeloma cells. We found that cell-surface-associated ?FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that ?FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated ?FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen. ? 2013 Biochemical Society.

AB - We have described the presence of cell-membrane-associated kFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-?FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for ? light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether ?FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of ?FLCs on the surface of myeloma cells. We found that cell-surface-associated ?FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that ?FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated ?FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen. ? 2013 Biochemical Society.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23822104

U2 - 10.1042/BJ20130575

DO - 10.1042/BJ20130575

M3 - Article

VL - 454

SP - 479

EP - 489

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -