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Santos, Taiz dos Reis ; Trujilho, Mariana Nascimento Romero ; Costa, Joao Pedro Martins Silva ; Dalzoto, Laurade Azevedo Maffeis ; Duarte, Ane Caroline Moreira ; Valdivia, Karolaine Stella Siqueirade Moraes ; Machado, Ana Juliade Oliveira ; Rios, Vitoria Caroline Domingues ; de Moraes, Tatiane Faustino ; Judice, Wagner Alves de Souza ; Marcondes, Marcelo Ferreira ; Machado, Mauricio Ferreira Marcondes

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS; v. 1873, n. 6, p. 10-pg., 2025-11-01.

Resumo

Metacaspases are members of the CD clan and share structural similarities with mammalian caspases but possess unique features. This study delves into the Candida albicans metacaspase CaMCA-Ia, a type I metacaspase. CaMCA-Ia demonstrates Ca2+-dependent autoprocessing and presents a hydrophobic N-terminal, which differs from that of type II metacaspases. Truncated CaMCA-Ia (CaMCA-Ia-Delta N86), lacking 86 N-terminal amino acids, undergoes gradual self-processing and intermolecular processing. Calcium addition induces multistep processing, leading to maturation. Like mammalian caspases, CaMCA-Ia-Delta N86 can activate other molecules, indicate intermolecular activation and accelerating maturation. Distinct binding sites for the full-length and truncated forms of CaMCA-Ia in interaction with Ca2+ underscore the N-terminal's role in altering calcium affinity. These findings enhance the understanding of metacaspases' intricate activation and maturation dynamics, offering insights into potential drug targets for pathogenic fungi. The CaMCA mutants D252A, D268A, D299A, and D268/ 269 A display varied responses to calcium, while the corresponding CaMCA-Ia-Delta N86 mutants exhibit different processing patterns. The D268/299 A mutant showed processing after 48 h of incubation with calcium. Alterations in CaMCA structure and function, such as the deletion of the N-terminus and changes in the aspartates at the calcium-binding site, provide important insights into how CaMCA enzymatic activity and autoprocessing are regulated. (AU)

• Processo FAPESP: 22/06394-0 - Obtenção e caracterização bioquímica de metacaspases recombinantes de protozoários de interesse clínico
• Beneficiário: Mauricio Ferreira Marcondes Machado
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/01503-2 - Avaliação dos efeitos de glicosaminoglicanos na atividade de inibidores de cisteíno proteases catepsinas
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/27813-8 - Desenvolvimento de inibidores de beta-lactamases de interesse clínico
• Beneficiário: Marcelo Ferreira Marcondes Machado
• Modalidade de apoio: Auxílio à Pesquisa - Regular