4.5 Article

Construction and analysis of a human testis/sperm-enriched interaction network: Unraveling the PPP1CC2 interactome

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1861, Issue 2, Pages 375-385

Publisher

ELSEVIER
DOI: 10.1016/j.bbagen.2016.11.041

Keywords

Testis; Spermatozoa; Protein-protein interaction network; Phosphoprotein phosphatase 1

Funding

  1. FCT - Fundacao para a Ciencia e Tecnologia [PTDC/DTP-PIC/0460/2012, PTDB/BBB-BQB/3804/2014]
  2. FEDER through Eixo I do Programa Operacional Fatores de Competitividade (POFC) do QREN [COMPETE: FCOMP-01-0124-FEDER-028692]
  3. FCT of the Portuguese Ministry of Science and Higher Education [SFRH/BD/81458/2011]
  4. Investigador mais centro from the project New Strategies Applied to Neuropathological Disorders [CENTRO-07-ST24-FEDER-002034]
  5. PRIME-XS consortium [PRIME-XS-0000111]
  6. Institute for Biomedicine iBiMED [UID/BIM/04501/2013]
  7. Fundação para a Ciência e a Tecnologia [SFRH/BD/81458/2011, PTDC/DTP-PIC/0460/2012] Funding Source: FCT

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Background: Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1CC tissue-specific alternative splice restricted to testicular germ cells and spermatozoa, is essential for spermatogenesis and spermatozoa motility. The key to understand PPP1CC2 regulation lies on the characterization of its interacting partners. Methods: We construct a testis/sperm-enriched protein interaction network and analyzed the topological properties and biological context of the network. Further the interaction of a potential target for pharmacological intervention was validated in human spermatozoa. Results: A total of 1778 proteins and 32,187 interactions between them were identified in the testis/sperm-enriched network. The network analysis revealed the members of functional modules that interact more tightly with each other. In the network, PPP1CC was located in the fourth maximum core part (k = 41) and had 106 direct interactors. Sixteen PPP1CC interactors were involved in spermatogenesis-related categories. Also, PPP1CC had 50 direct interactors, highly interconnected and many of them part of the network maximum core (k = 44), associated with motility-related annotations, including several previously uncharacterized interactors, such as, LMNA, JAK2 and RIPK3. Conclusions: In this study we integrated tissue-specific protein expression and protein-protein interaction data in order to identify key PPP1CC2 complexes for male reproductive functions. One of the most intriguing interactors was A-kinase anchor protein 4 (AKAP4), a testis-specific protein related to infertility phenotypes and involved in all major motility-related annotations. General significance: We demonstrated for the first time the interaction between PPP1CC2 and AKAP4 in human spermatozoa and the potential of the complex as contraceptive target. (C) 2016 Elsevier B.V. All rights reserved.

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