Sandbox Reserved 938
From Proteopedia
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==Introduction== | ==Introduction== | ||
| - | Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) forms an evultionarily conserved distinct family of growth factors together with the Cerebral Dopamine Neurotrophic Factor (CDNF) | + | Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) forms an evultionarily conserved distinct family of growth factors together with the Cerebral Dopamine Neurotrophic Factor (CDNF) (Lindholm and Saarma, 2010). MANF and also CDNF can repair dopamine neurons in different toxin-induced lesion models in vivo in rats (Voutilainen et al, 2009. MANF can protect neurons also in rat models of stroke (Airavaara et al, 2009). MANF also protects cardiac myocytes in myocardial infarction (Glembotski et al, 2012). |
| + | However, the mechanisms of the protective actions of MANF, including it's receptor, remain to be discovered. It is however known, that MANF is localized in the ER and is part of the unfolded protein (UPR) response cascade and is secreted upon ER-stress in vitro, also binding the ER chaperone GRP78 (Glembotski et al., 2012, Lindholm and Saarma, 2010, Apostolou et al., 2008, Mizobouchi et al., 2007). | ||
| - | In | + | In 2009 the crystal structure of MANF was solved by Parkash et al (Parkash et al, 2009), giving important insights into the function of MANF. The further content of this page is directed to dissecting the structure/function relation of the MANF protein. |
<StructureSection load='2W51' size='350' side='right' caption='MANF' scene='57/579708/Manf_rainbow/2'> | <StructureSection load='2W51' size='350' side='right' caption='MANF' scene='57/579708/Manf_rainbow/2'> | ||
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==The structure of MANF== | ==The structure of MANF== | ||
| - | MANF has 2 distinc and also functionally different domains, C-terminal and N-terminal, connected by an unstructured loop. There are 4 S-S bridges formed in the molecule, 3 of which in the N-terminal and 1 in the C-terminal domain. The structure suggests | + | MANF has 2 distinc and also functionally different domains, C-terminal and N-terminal, connected by an unstructured loop. There are 4 S-S bridges formed in the molecule, 3 of which in the N-terminal and 1 in the C-terminal domain. The structure suggests a dual function of the protein, since the two domains of which it consists, are rather different from one another and show structural similarity to functionally very distinct proteins. |
===N-terminal domain=== | ===N-terminal domain=== | ||
| - | Here is the <scene name='57/579708/N_zoom_rainbow/2'>N-terminal domain</scene> of the protein. MANF N-terminus is a saposin-like domain (SAPLIP). SAPLIPs, although they have a rather low sequence homology, have a high structural homology and seem to all share the ability to | + | Here is the <scene name='57/579708/N_zoom_rainbow/2'>N-terminal domain</scene> of the protein. MANF N-terminus is a saposin-like domain (SAPLIP). SAPLIPs, although they have a rather low sequence homology, have a high structural homology and seem to all share the ability to bind lipids (Hellman et al., 2012). However, since the biological receptor and interaction partners are either completely (receptor(s)) or largely (interactions with other proteins) unknown, the precise molecular mechanisms remain elusive. However, it has been proposed, that the neuroprotective ability of MANF may reside in it's N-terminal domain. |
===C-terminal domain=== | ===C-terminal domain=== | ||
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==MANF in disease== | ==MANF in disease== | ||
| - | MANF knock-out mouse has been generated and characterized, the results were published very recently [Reference], revealing a very intruiging phenotype, further confirming the beforementioned interactions and structure/function relations. | + | MANF knock-out mouse has been generated and characterized, the results were published very recently [Reference], revealing a very intruiging phenotype, further confirming the beforementioned interactions and structure/function relations. Namely, the global MANF knock-out develops a severe case of diabetes due to increased ER-stress response (Lindahl et al, 2014). The roles of MANF, proposed by the crystal structure of the C-terminal domain, have thus been confirmed by the in vivo studies. |
</StructureSection> | </StructureSection> | ||
==References== | ==References== | ||
| + | 1. Lindholm P and Saarma M. Novel CDNF/MANF family of neurotrophic factors, Developmental Neurobiology, 2010. | ||
| + | |||
| + | 2. Voutilainen MH, Bäck S, Pörsti E, Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M and Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease, Journal of Neuroscience, 2009. | ||
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| + | 3. Airavaara M, Shen H, Kuo CC, Peränen J, Saarma M, Hoffer B, Wang Y. Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats, Journal of Comparative Neurology, 2009. | ||
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| + | 4. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009. | ||
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| + | 5. Glembotski CC, Thuerauf DJ, Huang C, Vekich JA, Gottlieb RA, Doroudgar S. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. Journal of Biological Chemistry, 2012. | ||
| + | |||
| + | 6. Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Experimental Cell Research, 2008. | ||
| + | |||
| + | 7. Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A, Nagata K. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell Structure and Function, 2007. | ||
| + | |||
| + | 8. Hellman M, Arumäe U, Yu LY, Lindholm P, Peränen J, Saarma M, Permi P. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. The Journal of Biological Chemistry, 2010. | ||
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| + | 9. Lindahl M, Danilova T, Palm E, Lindholm P, Võikar V, Hakonen E, Ustinov J, Andressoo JO, Harvey BK, Otonkoski T, Rossi J, Saarma M. MANF Is Indispensable for the Proliferation and Survival of Pancreatic β Cells. Cell Reports, 2014. | ||
Revision as of 09:53, 12 May 2014
| This Sandbox is Reserved from 01/04/2014, through 30/06/2014 for use in the course "510042. Protein structure, function and folding" taught by Prof Adrian Goldman, Tommi Kajander, Taru Meri, Konstantin Kogan and Juho Kellosalo at the University of Helsinki. This reservation includes Sandbox Reserved 923 through Sandbox Reserved 947. |
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Introduction
Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) forms an evultionarily conserved distinct family of growth factors together with the Cerebral Dopamine Neurotrophic Factor (CDNF) (Lindholm and Saarma, 2010). MANF and also CDNF can repair dopamine neurons in different toxin-induced lesion models in vivo in rats (Voutilainen et al, 2009. MANF can protect neurons also in rat models of stroke (Airavaara et al, 2009). MANF also protects cardiac myocytes in myocardial infarction (Glembotski et al, 2012). However, the mechanisms of the protective actions of MANF, including it's receptor, remain to be discovered. It is however known, that MANF is localized in the ER and is part of the unfolded protein (UPR) response cascade and is secreted upon ER-stress in vitro, also binding the ER chaperone GRP78 (Glembotski et al., 2012, Lindholm and Saarma, 2010, Apostolou et al., 2008, Mizobouchi et al., 2007).
In 2009 the crystal structure of MANF was solved by Parkash et al (Parkash et al, 2009), giving important insights into the function of MANF. The further content of this page is directed to dissecting the structure/function relation of the MANF protein.
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References
1. Lindholm P and Saarma M. Novel CDNF/MANF family of neurotrophic factors, Developmental Neurobiology, 2010.
2. Voutilainen MH, Bäck S, Pörsti E, Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M and Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease, Journal of Neuroscience, 2009.
3. Airavaara M, Shen H, Kuo CC, Peränen J, Saarma M, Hoffer B, Wang Y. Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats, Journal of Comparative Neurology, 2009.
4. Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional, Protein Engineering, Design and Selection, 2009.
5. Glembotski CC, Thuerauf DJ, Huang C, Vekich JA, Gottlieb RA, Doroudgar S. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. Journal of Biological Chemistry, 2012.
6. Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Experimental Cell Research, 2008.
7. Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A, Nagata K. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell Structure and Function, 2007.
8. Hellman M, Arumäe U, Yu LY, Lindholm P, Peränen J, Saarma M, Permi P. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. The Journal of Biological Chemistry, 2010.
9. Lindahl M, Danilova T, Palm E, Lindholm P, Võikar V, Hakonen E, Ustinov J, Andressoo JO, Harvey BK, Otonkoski T, Rossi J, Saarma M. MANF Is Indispensable for the Proliferation and Survival of Pancreatic β Cells. Cell Reports, 2014.
