title: Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44.
abstract: Adiponectin, a collagenous hormone secreted abundantly from adipocytes, possesses potent antidiabetic and anti-inflammatory properties. Mediated by the conserved Cys(39) located in the variable region of the N terminus, the trimeric (low molecular weight (LMW)) adiponectin subunit assembles into different higher order complexes, e.g. hexamers (middle molecular weight (MMW)) and 12-18-mers (high molecular weight (HMW)), the latter being mostly responsible for the insulin-sensitizing activity of adiponectin. The endoplasmic reticulum (ER) chaperone ERp44 retains adiponectin in the early secretory compartment and tightly controls the oxidative state of Cys(39) and the oligomerization of adiponectin. Using cellular and in vitro assays, we show that ERp44 specifically recognizes the LMW and MMW forms but not the HMW form. Our binding assays with short peptide mimetics of adiponectin suggest that ERp44 intercepts and converts the pool of fully oxidized LMW and MMW adiponectin, but not the HMW form, into reduced trimeric precursors. These ERp44-bound precursors in the cis-Golgi may be transported back to the ER and released to enhance the population of adiponectin intermediates with appropriate oxidative state for HMW assembly, thereby underpinning the process of ERp44 quality control.
authors.affiliation: School of Biological Science, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hampe
authors.affiliation: School of Biological Science, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors.forename: Mazdak
authors.initials: M
authors.lastname: Radjainia
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, 999007 Hong Kong, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand; Institute for Innovation in Biotechnology, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.
authors.forename: Paul W R
authors.initials: PWR
authors.lastname: Harris
authors.affiliation: School of Biological Science, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors.forename: Ghader
authors.initials: G
authors.lastname: Bashiri
authors.affiliation: School of Biological Science, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors.forename: David C
authors.initials: DC
authors.lastname: Goldstone
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand; Institute for Innovation in Biotechnology, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, 999007 Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biological Science, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand. Electronic address: a.mitra@auckland.ac.nz.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D052242:Adiponectin / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D060066:Protein Interaction Maps; D055503:Protein Multimerization
chemical_list: D052242:Adiponectin; C520556:ERp44 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones
keywords: ER quality control; adiponectin; disulfide; peptide interaction; thiol