Opposing Intermolecular Tuning of Ca2+ Affinity for Calmodulin by Neurogranin and CaMKII Peptides
We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kina...
Uloženo v:
| Vydáno v: | Biophysical journal Ročník 112; číslo 6; s. 1105 |
|---|---|
| Hlavní autoři: | , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
28.03.2017
|
| ISSN: | 1542-0086, 1542-0086 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
| Tagy: |
Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
|
| Abstract | We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13-49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13-49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13-49 structures by matching the changes in the chemical shifts of CaM upon Ng13-49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13-49 by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13-49 and holoCaM-CaMKII delineates the importance of CaM's progressive mechanism of target binding on its Ca2+ binding affinities.We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13-49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13-49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13-49 structures by matching the changes in the chemical shifts of CaM upon Ng13-49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13-49 by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13-49 and holoCaM-CaMKII delineates the importance of CaM's progressive mechanism of target binding on its Ca2+ binding affinities. |
|---|---|
| AbstractList | We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13-49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13-49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13-49 structures by matching the changes in the chemical shifts of CaM upon Ng13-49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13-49 by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13-49 and holoCaM-CaMKII delineates the importance of CaM's progressive mechanism of target binding on its Ca2+ binding affinities.We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13-49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13-49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13-49 structures by matching the changes in the chemical shifts of CaM upon Ng13-49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13-49 by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13-49 and holoCaM-CaMKII delineates the importance of CaM's progressive mechanism of target binding on its Ca2+ binding affinities. |
| Author | Zhang, Pengzhi Trinh, Hoa Cheung, Margaret S Tripathi, Swarnendu |
| Author_xml | – sequence: 1 givenname: Pengzhi surname: Zhang fullname: Zhang, Pengzhi – sequence: 2 givenname: Swarnendu surname: Tripathi fullname: Tripathi, Swarnendu – sequence: 3 givenname: Hoa surname: Trinh fullname: Trinh, Hoa – sequence: 4 givenname: Margaret S surname: Cheung fullname: Cheung, Margaret S |
| BookMark | eNpNkD1PwzAYhC1UJNrCD2DziIQSXtux445VxUdEoQxlrlzndZXKtUOcDP33BMHAdKe7RzfcjExCDEjILYOcAVMPx3zfHnMOrMyB5cDhgkyZLHgGoNXkn78is5SOAIxLYFNiNm0bUxMOtAo9dqfo0Q7edHQ7hJ80Oroy_J4unWtC05-pi92Y-FOsB98Euj_Tdxy6eOjMyFMT6rF9e60q-oFt39SYrsmlMz7hzZ_OyefT43b1kq03z9Vquc6s0KrPGDo03JUCJBNaSF2WBTIshVgYYZ0qpF3AwgIC1soWCph2FgtZ78FoLhWfk7vf3baLXwOmfndqkkXvTcA4pB3TIzY-wAX_BgL4Wl0 |
| CitedBy_id | crossref_primary_10_1039_C7CP07399B crossref_primary_10_3389_fpsyt_2021_763032 crossref_primary_10_1186_s12284_024_00686_z crossref_primary_10_1016_j_bpj_2024_02_021 crossref_primary_10_3389_fmolb_2021_661322 crossref_primary_10_1016_j_bbapap_2018_03_007 crossref_primary_10_1002_pro_4955 crossref_primary_10_1074_jbc_RA118_006857 crossref_primary_10_1016_j_jmgm_2021_107875 crossref_primary_10_1371_journal_pone_0196662 |
| ContentType | Journal Article |
| Copyright | Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved. |
| Copyright_xml | – notice: Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved. |
| DBID | 7X8 |
| DOI | 10.1016/j.bpj.2017.01.020 |
| DatabaseName | MEDLINE - Academic |
| DatabaseTitle | MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Biology |
| EISSN | 1542-0086 |
| GroupedDBID | --- -DZ -~X .55 0R~ 23N 2WC 4.4 457 5GY 5RE 62- 6J9 7X8 AAEDT AAEDW AAKRW AALRI AAMRU AAVLU AAXUO ABDGV ABJNI ABMAC ACBEA ACGFO ACGFS ACGOD ACIWK ACNCT ACPRK ACVFH ADBBV ADCNI ADEZE ADVLN AENEX AEUPX AEXQZ AFPUW AFRAH AFTJW AGKMS AHMBA AIGII AITUG AKAPO AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ AOIJS APXCP AYCSE AZFZN BAWUL CS3 D0L DIK DU5 E3Z EBS EFKBS EJD F5P FCP FDB FRP HYE IH2 IXB JIG KQ8 L7B M41 N9A O-L O9- OK1 P2P RNS ROL RPM RWL SES SSZ TAE TBP TN5 WH7 WOQ WOW X7M YNY YWH ~02 |
| ID | FETCH-LOGICAL-c386t-1efea2f7305138358774e1e7339a3cf645c909c0e0ed6c46018fce45db0a82562 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 11 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000397969500009&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1542-0086 |
| IngestDate | Thu Oct 02 09:36:02 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 6 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c386t-1efea2f7305138358774e1e7339a3cf645c909c0e0ed6c46018fce45db0a82562 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | https://pubmed.ncbi.nlm.nih.gov/PMC5374985 |
| PQID | 1882500823 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_1882500823 |
| PublicationCentury | 2000 |
| PublicationDate | 2017-03-28 |
| PublicationDateYYYYMMDD | 2017-03-28 |
| PublicationDate_xml | – month: 03 year: 2017 text: 2017-03-28 day: 28 |
| PublicationDecade | 2010 |
| PublicationTitle | Biophysical journal |
| PublicationYear | 2017 |
| SSID | ssj0012501 |
| Score | 2.2848015 |
| Snippet | We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and... |
| SourceID | proquest |
| SourceType | Aggregation Database |
| StartPage | 1105 |
| Title | Opposing Intermolecular Tuning of Ca2+ Affinity for Calmodulin by Neurogranin and CaMKII Peptides |
| URI | https://www.proquest.com/docview/1882500823 |
| Volume | 112 |
| WOSCitedRecordID | wos000397969500009&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1bS8MwFA7qFHzxLt6J4JsEm7Rp0ycZ4nCIcw8T9jZyHRPXTrsJ-_ee9MIefBF8bJtCm3PJl_N95CB0wylANiVSkjqakogbTqRNFKEmDA2TnkwLymYTSa8nhsO0XxfcilpW2eTEMlGbXPsa-R0FKMhLXuh-9kl81yjPrtYtNNZRKwQo4706Ga5YBHihOi81YsRj94bVLPVdavbulV1JdWpn8CsXlwtMZ_e_n7aHdmpoiduVL-yjNZsdoK2q2eTyEMnXmVdoZWNcVgGnTV9cPFj42gjOHX6Q7Ba3nZtAnC8xwFm48zHNjVerY7XE5UkeY1jd4FJmBp6-PHe7uO-VMcYWR-it8zh4eCJ1gwWiQxHPCbXOSuYgyDmFnSoXgAUttUkYpjLULo64ToNUBzawJtYR7N2E0xYMqgIJvxyzY7SR5Zk9QRjSVMIiHTsR80hZqUQkDWCbONFCMWpP0XUzdyNwYM9KyMzmi2K0mr2zP4w5R9veaF4FxsQFajkIUnuJNvX3fFJ8XZX2_wH55LhY |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Opposing+Intermolecular+Tuning+of+Ca2%2B+Affinity+for+Calmodulin+by+Neurogranin+and+CaMKII+Peptides&rft.jtitle=Biophysical+journal&rft.au=Zhang%2C+Pengzhi&rft.au=Tripathi%2C+Swarnendu&rft.au=Trinh%2C+Hoa&rft.au=Cheung%2C+Margaret+S&rft.date=2017-03-28&rft.issn=1542-0086&rft.eissn=1542-0086&rft.volume=112&rft.issue=6&rft.spage=1105&rft_id=info:doi/10.1016%2Fj.bpj.2017.01.020&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1542-0086&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1542-0086&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1542-0086&client=summon |