Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 47, Pages 12483-12488Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1711486114
Keywords
TDRD2; TDRKH; PIWI; piRNA; methylation-independent
Categories
Funding
- Janssen, Merck Co. [1097737]
- Novartis Pharma AG [1097737]
- Genome Canada through the Ontario Genomics Institute [1097737]
- Innovative Medicines Initiative (European Union/European Federation of Pharmaceutical Industries and Associations) Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery [1097737, 115766]
- Bayer Pharma AG [1097737]
- Pfizer [1097737]
- NIH Grant [R01HD084494]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Japan Society for the Promotion of Science KAKENHI Grant [JP17K17673]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Boehringer Ingelheim [1097737]
- Wellcome Trust [1097737]
- Sao Paulo Research Foundation [1097737]
- Takeda [1097737]
- Ministry of Education, Culture, Sports, Science and Technology KAKENHI Grant [JP26113007]
- AbbVie [1097737]
- Grants-in-Aid for Scientific Research [17K17673] Funding Source: KAKEN
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The P-element-induced wimpy testis (PlWI)-interacting RNA (piRNA) pathway plays a central role in transposon silencing and genome protection in the animal germline. A family of Tudor domain proteins regulates the piRNA pathway through direct Tudor domain-PIWI interactions. Tudor domains are known to fulfill this function by binding to methylated PIWI proteins in an arginine methylation-dependent manner. Here, we report a mechanism of methylation-independent Tudor domain-PIWI interaction. Unlike most other Tudor domains, the extended Tudor domain of mammalian Tudor domain-containing protein 2 (TDRD2) preferentially recognizes an unmethylated arginine-rich sequence from PlWI-like protein 1 (PIWIL1). Structural studies reveal an unexpected Tudor domain-binding mode for the PIWIL1 sequence in which the interface of Tudor and staphylococcal nuclease domains is primarily responsible for PIWIL1 peptide recognition. Mutations disrupting the TDRD2-PIWIL1 interaction compromise piRNA maturation via 3'-end trimming in vitro. Our work presented here reveals the molecular divergence of the interactions between different Tudor domain proteins and PIWI proteins.
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